Fused pyrazole derivatives bieng protein kinase inhibitors

ABSTRACT

Compounds of Formula (I): salts or solvates or physiologically functional derivatives thereof, wherein Z is CH or N, and R 1 , (R 2 , and R 4  are various substituent groups, are protein kinase inhibitors.

[0001] The present invention relates to novel pyrazole derivatives,methods for their preparation, and their use to treat certain diseasesor conditions. In particular, the present invention relates to novelprotein kinase inhibitors.

[0002] Protein kinases play a critical role in the control of cellgrowth and differentiation, and are key mediators of cellular signalsleading to the production of growth factors and cytokines. See, forexample, Schiessinger and Ullrich, Neuron 1992, 9, 383. A partial,non-limiting list of such kinases includes abl, ATK, bcr-abl, Bik, Brk,Btk, c-kit, c-met, c-src, CDK1, CDK2, CDK4, CDK6, cRaf1, CSFLR, CSK,EGFR, ErbB2, ErbB3, ErbB4, ERK, Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4,FGFR5, Fgr, FLK-4, fit-1, Fps, Frk, Fyn, GSK, Hck, IGF-1R, INS-R, Jak,JNK, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, tie1 tie2, TRK,UL97, VEGF-R1, VEGF-R2, Yes and Zap70.

[0003] Protein kinases have been implicated as targets in centralnervous system disorders such as Alzheimer's (Mandelkow, E. M. et al.FEBS Lett. 1992, 314, 315; Sengupta, A. et al. Mol. Cell. Biochem. 1997,167, 99), pain sensation (Yashpal, K. J. Neurosci. 1995, 15, 3263-72),inflammatory disorders such as arthritis (Badger, J. Pharm. Exp. Ther.1996, 279, 1453), psoriasis (Dvir, et al, J. Cell Biol. 1991, 113, 857),bone diseases such as osteoporosis (Tanaka et al, Nature 1996, 383,528), cancer (Hunter and Pines, Cell 1994, 79, 573), atherosclerosis(Hajjar and Pomerantz, FASEB J. 1992, 6, 2933), thrombosis (Salari, FEBS1990, 263, 104), metabolic disorders such as diabetes (Borthwick, A. C.et al. Biochem. Biophys. Res. Commun. 1995, 210, 738), blood vesselproliferative disorders such as angiogenesis (Strawn et al. Cancer Res.1996, 56, 3540; Jackson et al. J. Pharm. Exp. Ther. 1998, 284, 687),restenosis (Buchdunger et al. Proc. Nat. Acad. Sci USA 1991, 92, 2258),autoimmune diseases and transplant rejection (Bolen and Brugge, Ann.Rev. Immunol. 1997, 15, 371), infectious diseases such as fungalinfections (Lum, R. T. PCT Int. Appl., WO 9805335 A1980212), chronicheart failure (Liu, I and Zhao, S. P. Int. J. Cardiology 1999, 69,77-82) and chronic obstructive pulmonary disease (Nguyen, L. T. et al.Clinical Nutr. 1999, 18, 255-257; Solar, N. et al. Eur. Respir. J. 1999,14, 1015-1022).

[0004] The p38 kinase is involved in the production of severalinflammatory factors and cytokines, including, for example, TNFα, IL-1,IL-6, IL-8, Cox-2 and matrix metalloproteinases. Inhibition of p38kinase results in the inhibition of production of these inflammatorymediators by cells treated with inflammatory stimuli. See, for example,Lee, Nature 1994, 372, 739, and Gallagher, Bioorganic & MedicinalChemistry 1997, 5, 49. This suggests that inhibition of p38 kinaseshould offer a method for the treatment of certain cytokine mediateddiseases (Dinarello, C. A. J. Biol. Regul. Homeostatic Agents 1997, 11,91).

[0005] The JNK kinases exist in three subtypes (JNK1, JNK2 and JNK3) andten isoforms. They are activated in response to extracellular stimulisuch as cytokines (e.g. Fas, IL1 and TNF) and inflammatory mediators,and by noxious stimuli such as UV, changes in calcium homeostasis andosmotic pressure, and by withdrawal of trophic factor. Their activationresults in the activation of the AP1 transcription factor complex; thegenes transcribed depend on the other components of the complex, and onthe specific JNK activated. In general, the JNK kinases are known tomediate apoptotic and inflammatory responses. JNK3 is a key mediator inthe apoptotic cell-death of neuronal cells and it appears to be involvedselectively in apoptosis in the brain rather than peripherally. JNKs 1and 2 are more widely distributed and although their normal function isnot precisely known, they are generally more closely linked to mediationof inflammation. This suggests that inhibition of JNK kinases shouldalso offer a method for the treatment of certain cytokine mediateddiseases.

[0006] WO 01/14375 published after the priority date of the presentapplication discloses various imidazo[1,2-A]pyridine andpyrazolo[2,3-A]pyridine derivatives which possess cell-cycle inhibitoryactivity.

[0007] The present invention provides novel compounds, compositions andmethods for treating diseases and conditions mediated by p38 kinase andfor treating diseases and conditions mediated by cytokines which areproduced by the activity of p38 kinase. Thus the present inventionprovides novel compounds, compositions and methods for treating, forexample, inflammatory diseases and conditions, and autoimmune diseasesand reactions.

[0008] The present invention also provides novel compounds, compositionsand methods for treating diseases and conditions mediated by JNK kinasesand for treating diseases and conditions mediated by cytokines which areproduced by the activity of JNK kinases. Thus the present inventionprovides novel compounds, compositions and methods for treating, forexample, inflammatory diseases and conditions, and autoimmune diseasesand reactions.

[0009] As used herein the terms “p38” or “p38 kinase” include allisoforms thereof, including the alpha, beta, beta2, gamma and deltaisoforms.

[0010] As used herein the terms “JNK” or “JNK kinase” include the threesubtypes JNK1, JNK2 and JNK3 and all isoforms thereof.

[0011] In one aspect, the present invention provides a compound ofFormula (I):

[0012] or a salt or solvate thereof or a physiologically functionalderivative thereof:

[0013] wherein

[0014] Z is CH or N;

[0015] a is 1 or 2;

[0016] b is 1, 2 or 3;

[0017] c is 1, 2 or 3;

[0018] each R¹ is independently selected from groups of the formula

—(X)_(d)—(CH₂)_(e)—R⁵

[0019] wherein

[0020] d is 0 or 1;

[0021] e is 0 to 6;

[0022] X is O, NR⁶ or S(O)_(f) where f is 0, 1 or 2;

[0023] R⁵ is hydrogen, halogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₁₂cycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxyl, cyano, nitro,trihalomethyl, NR⁷R⁸, C₆H₄NR⁷R⁸, C₆H₄(CH₂)NR⁷R⁸, C(O)R⁷, C(O)NR⁷R⁸,OC(o)R⁷, OC(O)NR⁷R⁸, CO₂R⁷, OCO₂R⁷, SO₂R⁷, SO₂NR⁷R⁸, C(═NR⁷)NR⁷R⁸,NR⁷(C═NR⁷)NR⁷R⁸, NHC(O)R⁷ or N(C₁₋₃alkyl)C(O)R⁷;

[0024] each R² is independently selected from hydrogen, cyano, halogen,trihalomethyl, OC₁₋₆alkyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,S(O)_(g)C₁₋₆alkyl where g is 0, 1 or 2, NC₁₋₆alkyl(C₁₋₆alkyl), hydroxylor nitro;

[0025] each R⁴ is independently selected from groups of the formula

—(Y)_(d)—(CH₂)_(e)—R³

[0026] wherein

[0027] d is 0 or 1;

[0028] e is 0 to 6;

[0029] Y is O or S(O)_(f) where f is 0, 1 or 2;

[0030] R³ is hydrogen, halogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₁₂cycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxyl, cyano, nitro,trihalomethyl, phthalamido, C₆H₄NR⁷R⁸ C₆H₄(CH₂)NR⁷R⁸, C(O)R⁷, C(O)NR⁷R⁸,OC(O)R⁷, OC(O)NR⁷R⁸, CO₂R⁷, OCO₂R⁷, SO₂R⁷, SO₂NR⁷R⁸ or C(═NR⁷)NR⁷R⁸;

[0031] R⁶ is H, C₁₋₆alkyl, C₂₋₆alkenyl, aryl, heteroaryl,C₃₋₁₂cycloalkyl, or heterocyclyl;

[0032] R⁷ and R⁸ are each independently H, C₁₈alkyl, C₂₋₆alkenyl,SO₂C₁₋₆alkyl, (CH₂)_(m)—C₃₋₁₂cycloalkyl, (CH₂)_(m)-aryl,(CH₂)_(m)-heterocyclyl, (CH₂)_(m)-heteroaryl, wherein m is 0, 1 or 2, ormay, together with the nitrogen atom to which they are bound, form aheterocyclyl group; and

[0033] wherein any of said alkyl, alkenyl and alkynyl groups may beoptionally substituted with up to three members selected from halogen,hydroxyl, oxo, cyano, NR⁷R⁸, C₁₋₆alkyl, OC₁₋₆alkyl, S(O)C₁₋₆alkyl,S(O)₂C₁₋₆alkyl and SO₂NR⁷R⁸; and

[0034] wherein any of said cycloalkyl, heterocyclyl, aryl, andheteroaryl groups may be optionally substituted with substituentsselected from a group consisting of C₁₋₆alkyl, C₁₋₆alkoxy,C₁₋₆alkylsulfenyl, C₁₋₆alkylsulfinyl, C₁₋₆alkylsulfonyl, hydroxy, oxo,mercapto, nitro, cyano, halogen, C₁₋₆perfluoroalkyl, amino optionallysubstituted by C₁₋₆alkyl, carbamoyl optionally substituted by C₁₋₆alkyl,NR⁷R⁸, carboxy and aminosulfonyl optionally substituted by C₁₋₆alkyl;

[0035] with the proviso that (R²)_(b), (R¹)_(a) and (R⁴)_(c) cannot allrepresent solely hydrogen substitution;

[0036] and with the proviso that when (R²)_(b) represents solelyhydrogen or methyl substitution, (R⁴)_(c) cannot represent solelyhydrogen substitution;

[0037] and with the proviso that R⁴ may not be located on the 7-positionof the pyrazolopyridine ring system as numbered below:

[0038] In a preferred embodiment, a salt or solvate of a compound offormula (I) will be a pharmaceutically acceptable salt or solvatethereof.

[0039] In another aspect, the present invention provides apharmaceutical composition comprising a compound of formula (I) or asalt or solvate thereof, or a physiologically functional derivativethereof, in admixture with one or more pharmaceutically acceptablecarriers, diluents or excipients.

[0040] In another aspect, the present invention provides a compound offormula (I) or a salt or solvate thereof, or a physiologicallyfunctional derivative thereof, for use in therapy.

[0041] The present invention provides compounds which inhibit or reducep38 kinase activity or which inhibit or reduce cytokine productionresulting from the activity of p38 kinase. Thus, in another aspect, thepresent invention provides for the use of a compound of formula (I) or asalt or solvate thereof, or a physiologically functional derivativethereof, for the preparation of a medicament for the treatment of acondition or disease state mediated by p38 kinase activity or mediatedby cytokines produced by the activity of p38 kinase.

[0042] The present invention provides compounds which inhibit or reduceJNK kinase activity or which inhibit or reduce cytokine productionresulting from the activity of JNK kinases. Thus, in another aspect, thepresent invention provides for the use of a compound of formula (I) or asalt or solvate thereof, or a physiologically functional derivativethereof, for the preparation of a medicament for the treatment of acondition or disease state mediated by JNK kinase activity or mediatedby cytokines produced by the activity of JNK kinase.

[0043] The present invention also provides compounds which inhibit orreduce both p38 and JNK kinase activity or which inhibit or reducecytokine production resulting from the activity of both p38 and JNKkinase. Thus, in another aspect, the present invention provides for theuse of a compound of formula (I) or a salt or solvate thereof, or aphysiologically functional derivative thereof, for the preparation of amedicament for the simultaneous treatment of two or more conditions ordisease states independently mediated by p38 and JNK kinase activity orindependently mediated by cytokines produced by the activity of p38 andJNK kinase.

[0044] In another aspect, the present invention provides a method fortreating a condition or disease mediated by p38 kinase activity ormediated by cytokines produced by the activity of p38 kinase using acompound of formula (I) or a salt or solvate thereof, or aphysiologically functional derivative thereof.

[0045] In another aspect, the present invention provides a method fortreating a condition or disease mediated by JNK kinase activity ormediated by cytokines produced by the activity of JNK kinase using acompound of formula (I) or a salt or solvate thereof, or aphysiologically functional derivative thereof.

[0046] In another aspect, the present invention provides a method fortreating two or more conditions or diseases independently mediated byp38 and JNK kinase activity or independently mediated by cytokinesproduced by the activity of p38 and JNK kinase using a compound offormula (I) or a salt or solvate thereof, or a physiologicallyfunctional derivative thereof.

[0047] As used herein, the term “physiologically functional derivative”refers to any pharmaceutically acceptable derivative of a compound ofthe present invention, for example, an ester or an amide, which uponadministration to a mammal, such as a human, is capable of providing(directly or indirectly) such a compound or an active metabolitethereof. Such derivatives are clear to those skilled in the art, withoutundue experimentation, and with reference to the teaching of Burger'sMedicinal Chemistry And Drug Discovery, 5^(th) Edition, Vol 1:Principles And Practice, which is incorporated herein by reference.

[0048] As used herein, the terms “alkyl” and “alkylene” refer tostraight or branched hydrocarbon chains containing the specified numberof carbon atoms. For example, C₁₋₆alkyl means a straight or branchedalkyl containing at least 1, and at most 6, carbon atoms. Examples of“alkyl” as used herein include, but are not limited to, methyl, ethyl,n-propyl, n-butyl, n-pentyl, isobutyl, and isopropyl. Examples of“alkylene” as used herein include, but are not limited to, methylene,ethylene, propylene and butylene. The said alkyl groups may beoptionally substituted with up to three members selected from halogen,hydroxyl, oxo, cyano, NR⁷R⁸, C₁₋₆alkyl, OC₁₋₆alkyl, S(O)C₁₋₆alkyl,S(O)₂C₁₋₆alkyl and SO₂NR ⁷R⁸. A preferred substituent for said alkylgroups is C₁₋₄alkyl, more preferably n-butyl. Thus a preferredsubstituted alkyl group is n-octyl.

[0049] As used herein, the term “alkenyl” refers to straight or branchedhydrocarbon chains containing the specified number of carbon atoms andcontaining at least one double bond. For example, C₂₋₆alkenyl means astraight or branched alkenyl containing at least 2, and at most 6,carbon atoms and containing at least one double bond. Examples of“alkenyl” as used herein include, but are not limited to ethenyl andpropenyl. The said alkenyl groups may be optionally substituted with upto three members selected from halogen, hydroxyl, oxo, cyano, NR⁷R⁸,C₁₋₆alkyl, OC₁₋₆alkyl, S(O)C₁₋₆alkyl, S(O)₂C₁₋₆alkyl and SO₂NR⁷R⁸.

[0050] As used herein, the term “alkynyl” refers to straight or branchedhydrocarbon chains containing the specified number of carbon atoms andcontaining at least one triple bond. For example, C₂₋₆alkynyl means astraight or branched alkynyl containing at least 2, and at most 6,carbon atoms and containing at least one triple bond. Examples of“alkynyl” as used herein include, but are not limited to, ethynyl andpropynyl. The said alkynyl groups may be optionally substituted with upto three members selected from halogen, hydroxyl, oxo, cyano, NR⁷R⁸,C₁₋₆alkyl, OC₁₋₆alkyl, S(O)C₁₋₆alkyl, S(O)₂C₁₋₆alkyl and SO₂NR⁷R⁸.

[0051] As used herein, the term “cycloalkyl” refers to a non-aromatichydrocarbon ring having from three to twelve carbon atoms. The said ringmay optionally contain up to three carbon-carbon double bonds.“Cycloalkyl” includes by way of example cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Preferredcycloalkyls are cyclopentyl and cyclohexyl. The said ring may beoptionally substituted with substituents selected from a groupconsisting of C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkylsulfenyl,C₁₋₆alkylsulfinyl, C₁₋₆alkylsulfonyl, hydroxy, oxo, mercapto, nitro,cyano, halogen, C₁₋₆perfluoroalkyl, amino optionally substituted byC₁₋₆alkyl, carbamoyl optionally substituted by C₁₋₆alkyl, NR⁷R⁸,carboxy, aminosulfonyl optionally substituted by C₁₋₆alkyl. A preferredsubstituent for said cycloalkyl groups is C₁₋₄alkyl, more preferablymethyl. Thus a preferred substituted cycloalkylalkyl group ismethylcyclopentyl, more preferably 3-methylcyclopentyl. As used herein,the terms “heterocycle”, “heterocyclyl” and “heterocyclic” refer to amonocyclic five to seven membered non-aromatic hydrocarbon ring or to afused bicyclic non-aromatic hydrocarbon ring system comprising two ofsuch monocyclic five to seven membered non-aromatic hydrocarbon rings.The ring or rings containing at least one heteroatom selected from 0, S,or N where N-oxides, sulfur oxides and sulfur dioxides are permissibleheteroatom substitutions. The said ring system may optionally contain upto three carbon-carbon, or carbon-nitrogen, double bonds. The said ringsystem may optionally be fused to one or more benzene rings. Examples ofheterocycles include, but are not limited to, tetrahydrofuran,dihydropyran, tetrahydropyran, pyran, oxetane, thietane, 1,4-dioxane,1,3-dioxane, 1,3-dioxalane, homopiperidine, piperidine, piperidine fusedto a benzene ring, piperazine, tetrahydropyrimidine, pyrrolidine,imidazoline, morpholine, thiomorpholine, thioxane, thiazolidine,oxazolidine, tetrahydrothiopyran, tetrahydrothiophene, and the like.Preferred heterocycles include morpholine, pyrrolidine, imidazolidine,homopiperidine, piperidine, piperidine fused to a benzene ring,piperazine, tetrahydropyran and tetrahydrothiopyran. The said ringsystem may be optionally substituted with substituents selected from agroup consisting of C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkylsulfenyl,C₁₋₆alkylsulfinyl, C₁₋₆alkylsulfonyl, hydroxy, oxo, mercapto, nitro,cyano, halogen, C₁₋₆perfluoroalkyl, amino optionally substituted byC₁₋₆alkyl, carbamoyl optionally substituted by C₁₋₆alkyl, NR⁷R⁸,carboxy, aminosulfonyl optionally substituted by C₁₋₆alkyl. Preferredsubstituents for said heterocyclyl groups are oxo and C₁₋₆alkyl, morepreferably methyl, n-propyl and isopropyl. Thus preferred substitutedheterocyclyl groups are imidazolidine-2,5-dione, 2-methylpiperidine,N-methylpiperazine, N-propylpiperazine and N-isopropylpiperazine.

[0052] As used herein, the term “aryl” refers to an optionallysubstituted phenyl or naphthyl ring. Said rings may be optionallysubstituted with substituents selected from a group consisting ofC₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkylsulfenyl, C₁₋₆alkylsulfinyl,C₁₋₆alkylsulfonyl, hydroxy, oxo, mercapto, nitro, cyano, halogen,C₁₋₆perfluoroalkyl, amino optionally substituted by C₁₋₆alkyl, carbamoyloptionally substituted by C₁₋₆alkyl, NR⁷R⁸, carboxy, aminosulfonyloptionally substituted by C₁₋₆alkyl.

[0053] As used herein, the term “heteroaryl” refers to a monocyclic fiveto seven membered aromatic ring, or to a fused bicyclic aromatic ringsystem comprising two of such monocyclic five to seven membered aromaticrings. These heteroaryl rings contain one or more nitrogen, sulfur, oroxygen heteroatoms, where N-oxides and sulfur oxides and dioxides arepermissible heteroatom substitutions. Examples of “heteroaryl” usedherein include furan, thiophene, pyrrole, imidazole, pyrazole, triazole,tetrazole, thiazole, oxazole, isoxazole, oxadiazole, thiadiazole,isothiazole, pyridine, pyridazine, pyrazine, pyrimidine, quinoline,isoquinoline, benzofuran, benzothiophene, indole, and indazole.Preferred heteroaryl groups include furan, pyrrole, imidazole, pyridine,pyrimidine, and thiophene. The rings are optionally substituted withsubstituents selected from a group consisting of C₁₋₆alkyl, C₁₋₆alkoxy,C₁₋₆alkylsulfenyl, C₁₋₆alkylsulfinyl, C₁₋₆alkylsulfonyl, hydroxy, oxo,mercapto, nitro, cyano, halogen, C₁₋₆perfluoroalkyl, amino optionallysubstituted by C₁alkyl, carbamoyl optionally substituted by C₁₋₆alkyl,NR⁷R⁸, carboxy, aminosulfonyl optionally substituted by C₁₋₆alkyl.

[0054] As used herein, the term “alkoxy” refers to the group R_(a)O—,where R_(a) is alkyl as defined above.

[0055] As used herein, the term “alkylsulfenyl” refers to the groupR_(a)S—, where R_(a) is alkyl as defined above.

[0056] As used herein, the term “alkylsulfinyl” refers to the groupR_(a)S(O)—, where R_(a) is alkyl as defined above.

[0057] As used herein, the term “alkylsulfonyl” refers to the groupR_(a)SO₂—, where R_(a) is alkyl as defined above.

[0058] As used herein, the terms “halogen” or “halo” refer to theelements fluorine, chlorine, bromine and iodine. Preferred halogens arefluorine, chlorine and bromine. A particularly preferred halogen isfluorine.

[0059] As used herein, the term “optionally” means that the subsequentlydescribed event(s) may or may not occur, and includes both event(s)which occur and events that do not occur.

[0060] As used herein, the term “substituted” refers to substitutionwith the named substituent or substituents, multiple degrees ofsubstitution being allowed unless otherwise stated.

[0061] As used herein, the terms “contain” or “containing” can refer toin-line substitutions at any position along the above-defined alkyl,alkenyl, alkynyl or cycloalkyl substituents with one or more of any ofO, S, SO, SO₂, N, or N-alkyl, including, for example, —CH₂—O—CH₂—,—CH₂—SO₂—CH₂—, —CH₂—NH—CH₂— and so forth.

[0062] As used herein, the term “solvate” refers to a complex ofvariable stoichiometry formed by a solute (in this invention, a compoundof formula (I) or a salt thereof) and a solvent. Such solvents for thepurpose of the invention may not interfere with the biological activityof the solute. Examples of suitable solvents include water, methanol,ethanol and acetic acid. Preferably the solvent used is apharmaceutically acceptable solvent. Examples of suitablepharmaceutically acceptable solvents include water, ethanol and aceticacid. Most preferably the solvent used is water.

[0063] Certain compounds of formula (I) may exist in stereoisomericforms (e.g. they may contain one or more asymmetric carbon atoms or mayexhibit cis-trans isomerism). The individual stereoisomers (enantiomersand diastereomers) and mixtures of these are included within the scopeof the present invention. The present invention also covers theindividual isomers of the compounds represented by formula (I) asmixtures with isomers thereof in which one or more chiral centres areinverted. Likewise, it is understood that compounds of formula (I) mayexist in tautomeric forms other than that shown in the formula and theseare also included within the scope of the present invention.

[0064] In one embodiment, Z is CH. This provides compounds of formula(II) below:

[0065] In the embodiments represented by formula (II) when a is 1, themost preferred location for R¹ is on one of the carbon atoms closest tothe pyridyl nitrogen, i.e. in the 2-position. This provides compounds offormula (III) below:

[0066] In the embodiments represented by formula (11) when a is 2, themost preferred locations for the R¹ groups are on the two carbon atomsclosest to the pyridyl nitrogen, i.e. in the 2- and 6-positions.

[0067] In another embodiment, Z is N. This provides compounds of formula(IV) below:

[0068] In the embodiments represented by formula (IV) when a is 1, apreferred location for R¹ is on the carbon atom between the pyrimidylnitrogens, i.e. in the 2-position. This provides compounds of formula(V) below:

[0069] In the embodiments represented by formula (IV) when a is 1,another preferred location for R¹ is illustrated by compounds of formula(VI) below:

[0070] In a preferred embodiment, when a is 2, at least one of the R¹groups is F.

[0071] Preferably a is 1.

[0072] In an embodiment, R¹ is selected from hydrogen or a halogen,preferably fluorine.

[0073] In another embodiment, R¹ is selected from groups of the formula—O—(CH₂)_(e)—R⁵

[0074] wherein

[0075] e is 0 to 6, preferably 0 or 1; and

[0076] R⁵ is C₁₋₆alkyl (preferably methyl or n-butyl), aryl (preferablyphenyl), or trihalomethyl (preferably trifluoromethyl). Thus preferredembodiments of R¹ include OMe, O^(n)Bu, OPh and OCH₂CF₃.

[0077] In another embodiment, R¹ is selected from groups of the formula—S(O)_(f)—R⁵

[0078] wherein

[0079] f is 0, 1 or 2; and

[0080] R⁵ is C₁₋₆alkyl (preferably methyl). Thus preferred embodimentsof R¹ include SMe, SOMe and S(O)₂Me.

[0081] In another embodiment, R¹ is selected from groups of the formula

—NR⁶—(CH₂)_(e)—R⁵

[0082] wherein

[0083] e is 0 to 6; and

[0084] R⁵ is hydrogen, halogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₁₂cycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxyl, cyano, nitro,trihalomethyl, NR⁷R⁸, C₆H₄NR⁷R⁸, C₆H₄(CH₂)NR⁷R⁸, C(O)R⁷, C(O)NR⁷R⁸,OC(O)R⁷, OC(O)NR⁷R⁸, CO₂R⁷, OCO₂R⁷, SO₂R⁷, SO₂NR⁷R⁸, C(═NR⁷)NR⁷R⁸,NR⁷(C═NR ⁷)NR⁷R⁸, NHC(O)R⁷ or N(C₁₋₃alkyl)C(O)R⁷;

[0085] R⁶ is H, C₁₋₆alkyl, C₂₋₆alkenyl, aryl, heteroaryl,C₃₋₁₂cycloalkyl, or heterocyclyl, R⁷ and R⁸ are each independently H,C₁₋₈alkyl, C₂₋₆alkenyl, SO₂C₁₋₆alkyl, (CH₂)_(m)—C₃₋₁₂cycloalkyl,(CH₂)_(m)-aryl, (CH₂)_(m)-heterocyclyl, (CH₂)_(m)-heteroaryl, whereinm=0, 1 or 2, or may, together with the nitrogen atom to which they arebound, form a heterocyclyl group.

[0086] In a preferred embodiment, R¹ is selected from groups of theformula

—NR⁶—(CH₂)_(e)—R⁵

[0087] wherein

[0088] e is 0 to 6; and

[0089] R⁵ is hydrogen, halogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₁₂cycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxyl, cyano, nitro,trihalomethyl, NR⁷R⁸, C₆H₄NR⁷R⁸, C₆H₄(CH₂)NR⁷R⁸, C(O)R⁷, C(O)NR⁷R⁸,OC(O)R⁷, OC(O)NR⁷R⁸, CO₂R⁷, OCO₂R⁷, SO₂R⁷, SO₂NR⁷R⁸, C(═NR⁷)NR⁷R⁸,NR⁷(C═NR ⁷)NR⁷R⁸, NHC(O)R⁷ or N(C₁₋₃alkyl)C(O)R⁷;

[0090] R⁶ is H or C₁₋₆alkyl (preferably methyl);

[0091] R⁷ and R⁸ are each independently H, C₁₋₈alkyl, C₂₋₆alkenyl,SO₂C₁₋₆alkyl, (CH₂)_(m)—C₃₋₁₂cycloalkyl, (CH₂)_(m)-aryl,(CH₂)_(m)-heterocyclyl, (CH₂)_(m)-heteroaryl, wherein m=0, 1 or 2, ormay, together with the nitrogen atom to which they are bound, form aheterocyclyl group.

[0092] In a preferred embodiment, R¹ is selected from groups of theformula

—N(Me)—(CH₂)_(e)—R⁵

[0093] wherein

[0094] e is 0 to 6 (preferably 0); and

[0095] R⁵ is C₁₋₆alkyl (preferably methyl). Thus a preferred embodimentof R¹ is N(Me)₂.

[0096] In a preferred embodiment, R¹ is selected from groups of theformula

—NH—(CH₂)_(e)—R⁵

[0097] wherein

[0098] e is 0 to 6; and

[0099] R⁵ is hydrogen, halogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₁₂cycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxyl, cyano, nitro,trihalomethyl, NR⁷R⁸, C₆H₄NR⁷R⁸, C₆H₄(CH₂)NR⁷R⁸, C(O)R⁷, C(O)NR⁷R⁸,OC(O)R⁷, OC(O)NR⁷R⁸, CO₂R⁷, OCO₂R⁷, SO₂R⁷, SO₂NR⁷R⁸, C(═NR⁷)NR⁷R⁸,NR⁷(C═NR⁷)NR⁷ R⁸, NHC(O)R⁷ or N(C₁₋₃alkyl)C(O)R⁷;

[0100] R⁷ and R⁸ are each independently H, C₁₋₈alkyl, C₂₋₆alkenyl, SO₂C,alkyl, (CH₂)_(m)—C₃₋₁₂cycloalkyl, (CH₂)_(m)-aryl,(CH₂)_(m)-heterocyclyl, (CH₂)_(m)-heteroaryl, wherein m=0, 1 or 2, ormay, together with the nitrogen atom to which they are bound, form aheterocyclyl group.

[0101] In a preferred embodiment, R¹ is selected from groups of theformula —NH—R⁵

[0102] wherein

[0103] R⁵ is hydrogen, C₁₋₆alkyl (preferably propyl, iso-propyl,n-butyl, n-pentyl or n-hexyl), C₂₋₆alkenyl (preferably propenyl),C₃₋₁₂cycloalkyl (preferably cyclopropyl, cyclopentyl or cyclohexyl),aryl (preferably phenyl) or substituted aryl (preferably4-fluorophenyl).

[0104] In a preferred embodiment, R¹ is selected from groups of theformula

—NH—(CH₂)_(e)—R⁵

[0105] wherein

[0106] e is 1 to 6 (preferably 1, 2, 3 or 4, more preferably 1, 2 or 3);and

[0107] R⁵ is heterocyclyl (preferably piperidine, homopiperidine,piperazine, morpholine, pyrolidine or imidazolidine), aryl (preferablyphenyl), substituted aryl (preferably 4-chlorophenyl or4-methoxyphenyl), heteroaryl (preferably pyridine or imidazole),hydroxyl, trihalomethyl (preferably trifluoromethyl). Thus preferredembodiments of R¹ include NHCH₂Ph, NHCH₂(4-chlorophenol),NHCH₂(4-methoxyphenol), NH(CH₂)₂OH, NH(CH₂)₃OH,

[0108] A particularly preferred embodiment of R¹ is NH(CH₂)₃OH.

[0109] In a preferred embodiment, R¹ is selected from groups of theformula

—NH—(CH₂)_(e)—R⁵

[0110] wherein

[0111] e is 1 to 6 (preferably 1, 2, 3 or 4); and

[0112] R⁵ is NR⁷R⁸, C₆H₄NR⁷R⁸, C₆H₄(CH₂)NR⁷R⁸, C(O)NR⁷R⁸, OC(O)NR⁷R⁸,SO₂R⁷, SO₂NR⁷R⁸, NHC(O)R⁷ or N(C₁₋₃alkyl)C(O)R⁷;

[0113] R⁷ and R⁸ are each independently H, C₁₋₈alkyl, C₂₋₆alkenyl,SO₂C₁₋₆alkyl, (CH₂)_(m)—C₃₋₁₂cycloalkyl, (CH₂)_(m)-aryl,(CH₂)_(m)-heterocyclyl, (CH₂)_(m)-heteroaryl, wherein m=0, 1 or 2, ormay, together with the nitrogen atom to which they are bound, form aheterocyclyl group.

[0114] In a preferred embodiment, R¹ is selected from groups of theformula

—NH—(CH₂)_(e)—R⁵

[0115] wherein

[0116] e is 2, 3 or 4 and R⁵ is NR⁷R₅ and wherein R⁷ and R⁸ are eachindependently selected from H, C₁₋₄alkyl, S(Q)₂C₁₋₄alkyl,(CH₂)_(m)—C₃₋₈cycloalkyl, (CH₂)_(m)-aryl, (CH₂)_(m)-heterocyclyl, and(CH₂)_(m)-heteroaryl, wherein m=0, 1 or 2.

[0117] In a further preferred embodiment, R¹ is selected from groups ofthe formula

—NH—(CH₂)_(e)—R⁵

[0118] wherein

[0119] e is 2, 3 or 4, preferably 3, and R⁵ is NR⁷R⁸ wherein R⁷ and R⁸are each independently selected from H and C₁₋₄alkyl. More preferably R⁷and R⁸ are each independently selected from H, methyl, ethyl, n-propyl,iso-propyl, and butyl. Most preferably R⁵ is represented by a groupselected from any one of the following: amino, methylamino,dimethylamino, ethylamino, diethylamino, n-propylamino,di(n-propyl)amino, iso-propylamino, di(iso-propyl)amino and butylamino.In a further embodiment, any of said C₁₋₄alkyl groups may be optionallysubstituted by one or two groups selected from, oxo, hydroxy, cyano,S(O)C₁₋₄alkyl, S(O)₂C₁₋₄alkyl, OC₁₋₄alkyl, C₁₋₄alkyl and NR⁷R⁸ whereinR⁷ and R⁸ are each independently selected from H and C₁₋₄alkyl. Apreferred substituent for said alkyl groups is C₁₋₄alkyl, morepreferably n-butyl. Thus R⁵ is preferably represented by the groupn-octylamino.

[0120] In a further preferred embodiment, R¹ is selected from groups ofthe formula

—NH—(CH₂)_(e)—R⁵

[0121] wherein

[0122] e is 2, 3 or 4, preferably 3, and R⁵ is NR⁷R⁸ wherein either R⁷or R⁸ is represented by the group (CH₂)_(m)—C₃₋₈cycloalkyl wherein m is0, 1 or 2, preferably 0 or 1, more preferably 0. More preferably, eitherR⁷ or R⁸ represent cyclopentyl or cyclohexyl. Most preferably R⁵ isrepresented by a group selected from any one of the following:NH-cyclopentyl, NH—CH₂-cyclopentyl and NH-cyclohexyl. In a furtherembodiment, any of said C₃₋₈cycloalkyl groups may be optionallysubstituted by one or two groups selected from, oxo, hydroxy, cyano,S(O)C, ₄alkyl, S(O)₂C₁₋₄alkyl, OC₁₋₄alkyl, C₁₋₄alkyl and NR⁷R⁸ whereinR⁷ and R⁸ are each independently selected from H and C₁₋₄alkyl. Apreferred substituent for said alkyl groups is C₁₋₄alkyl, morepreferably methyl. Thus R⁵ is preferably represented by the groupNH-(3-methyl-cyclopentyl).

[0123] In a further preferred embodiment, R¹ is selected from groups ofthe formula

—NH—(CH₂)_(e)—R⁵

[0124] wherein

[0125] e is 2, 3 or 4, preferably 3, and R⁵ is NR⁷R⁸ wherein either R⁷or R⁸ is represented by the group (CH₂)_(m)-aryl wherein m is 0, 1 or 2,preferably 0 or 1. More preferably, R⁷ or R⁸ represent phenyl or benzyl.Most preferably R⁵ is represented by a group selected from any one ofthe following: N(Me)-phenyl and N(Me)-benzyl. In a further embodiment,any of said aryl groups may be optionally substituted by one or twogroups selected from, oxo, hydroxy, cyano, S(O)C₁₋₄alkyl,S(O)₂C₁₋₄alkyl, OC₁₋₄alkyl, C₁₋₄alkyl and NR⁷R⁸ wherein R⁷ and R⁸ areeach independently selected from H and C₁₋₄alkyl.

[0126] In a further preferred embodiment, R¹ is selected from groups ofthe formula

—NH—(CH₂)_(e)—R⁵

[0127] wherein

[0128] e is 2, 3 or 4, preferably 3, and R⁵ is NR⁷R⁸ wherein either R⁷or R⁸ is represented by the group (CH₂)_(m)-heterocyclyl wherein m is 0,1 or 2, preferably 0 or 2. More preferably R⁷ or R⁸ representpiperidine, piperazine, morpholine, tetrahydropyran ortetrahydrothiopyran. Most preferably R⁵ is represented by a groupselected from any one of the following:

[0129] In a further embodiment, any of said heterocyclyl groups may beoptionally substituted by one or two groups selected from, oxo, hydroxy,cyano, S(O)C₁₋₄alkyl, S(O)₂C₁₋₄alkyl, OC₁₋₄alkyl, C₁₋₄alkyl and NR⁷R⁸wherein R⁷ and R⁸ are each independently selected from H and C₁₋₄alkyl.

[0130] In a further preferred embodiment, R¹ is selected from groups ofthe formula

—NH—(CH₂)_(e)—R⁵

[0131] wherein

[0132] e is 2, 3 or 4, preferably 3, and R⁵ is NR⁷R⁸ wherein either R⁷or R⁸ are represented by the group (CH₂)_(m)-heteroaryl wherein m is 0,1 or 2, preferably 1. More preferably R⁷ or R⁸ represent furan, pyrrole,imidazole or pyridine. Most preferably R⁵ is represented by the group:

[0133] In a further embodiment, any of said heteroaryl groups may beoptionally substituted by one or two groups selected from, oxo, hydroxy,cyano, S(O)C₁₋₄alkyl, S(O)₂C₁₋₄alkyl, OC₁₋₄alkyl, C₁₋₄alkyl and NR⁷R⁸wherein R⁷ and R⁸ are each independently selected from H and C₁₋₄alkyl.

[0134] In a further preferred embodiment, R¹ is selected from groups ofthe formula

—NH—(CH₂)_(e)—R⁵

[0135] wherein

[0136] e is 2, 3 or 4, preferably 3, and R⁵ is NR⁷R⁸ wherein either R⁷or R⁸ are represented by the group S(O)₂C₁₋₄alkyl. More preferably R⁷ orR⁸ represent S(O)₂Me. In a further embodiment, any of said C₁₋₄alkylgroups may be optionally substituted by one or two groups selected from,oxo, hydroxy, cyano, S(O)C₁₋₄alkyl, S(O)₂C₁₋₄alkyl, OC₁₋₄alkyl,C₁₋₄alkyl and NR⁷R⁸ wherein R⁷ and R⁸ are each independently selectedfrom H and C₁₋₄alkyl.

[0137] In a preferred embodiment, R¹ is selected from groups of theformula

—NH—(CH₂)_(e)—R⁵

[0138] wherein

[0139] e is 2, 3 or 4, preferably 2 or 3, more preferably 3, and R⁵ isNR⁷R⁸ wherein both R⁷ and R⁸ are taken together with the N atom to whichthey are bonded to form a heterocyclyl group optionally fused to abenzene ring. Preferably, said heterocyclyl group is selected frompiperidine, homopiperidine, piperazine, morpholine, pyrolidine andimidazolidine each of which may be optionally fused to a benzene ring.Most preferably R⁵ is represented by a group selected from any one ofthe following:

[0140] In a further embodiment, any of said heterocyclyl groups may beoptionally substituted by one or two groups selected from, oxo, hydroxy,cyano, S(O)C₁₋₄alkyl, S(O)₂C₁₋₄alkyl, OC₁₋₄alkyl, C₁₋₄alkyl and NR⁷R⁸wherein R⁷ and R⁸ are each independently selected from H and C₁₋₄alkyl.Preferred substituents for said alkyl groups are oxo and C₁₋₄alkyl, morepreferably methyl, ethyl, propyl or iso-propyl. Thus R⁵ is preferablyrepresented by a group selected from any one of the following:

[0141] In a preferred embodiment b is 1 or 2.

[0142] In a more preferred embodiment each R² is independently selectedfrom hydrogen, cyano, halogen, trihalomethyl or OC₁₋₆alkyl.

[0143] In a more preferred embodiment the R² substituent(s) are in themeta- and/or para-position(s) relative to the bond to thepyrazolopyridine ring system. In a preferred embodiment, each R² isselected from chloro, fluoro and trifluoromethyl groups. In a morepreferred embodiment, (R²)_(b) is represented by one or two substituentsselected from F or Cl. In a further preferred embodiment, (R²)_(b) isrepresented by a CF₃ substituent. In a most preferred embodiment,(R²)_(b) and the phenyl ring to which such group(s) is/are bonded isselected from 3-chloro-4-fluorophenyl, 3-chlorophenyl, 4-fluorophenyland 4-trifluoromethylphenyl. In an especially preferred embodiment,(R²)_(b) and the phenyl ring to which such group(s) is/are bonded is4-fluorophenyl.

[0144] In a preferred embodiment c is 1.

[0145] In a preferred embodiment R⁴ is hydrogen.

[0146] In a preferred embodiment where c is 1 and R⁴ is not hydrogen, R⁴is bonded to the 5-position or the 6-position as those positions areshown below.

[0147] In another preferred embodiment, R⁴ is selected from C₁₋₆alkyl(preferably methyl) bonded to the 4-, 5- or 6-positions, halogen(preferably bromo, chloro or fluoro, more preferably fluoro) bonded tothe 4-, 5- or 6-positions (preferably the 6-position), CN bonded to the6-position, or trihalomethyl (preferably trifluoromethyl) bonded to the6-position. Most preferably R⁴ is fluoro bonded to the 6-position.

[0148] In another preferred embodiment R⁴ is selected from groups of theformula

—CH₂—R

[0149] wherein

[0150] R³ is selected from OH, phthalamido or OC(O)R⁷ wherein R⁷ is aryl(preferably phenyl) or heteroaryl (preferably pyridine or thiophene)optionally substituted with halogen (preferably bromine or chlorine),amino, C₁₋₆alkylsulfonyl (preferably methylsulfonyl), aminosulfonyl,C₁₋₆alkyl (preferably methyl) or OC₁₋₆alkyl (preferably methoxy). Thuspreferred R⁴ groups include the following:

[0151] In another preferred embodiment, R⁴ is selected from groups ofthe formula

—O—(CH₂)_(e)—R³

[0152] wherein

[0153] e is 0 or 1, and R³ is selected from hydrogen, C₁₋₆alkyl(preferably methyl or n-butyl), aryl (preferably phenyl), trihalomethyl(preferably trifluoromethyl) or C(O)R⁷ wherein R⁷ is selected from(CH₂)_(m)-heteroaryl wherein m is 0 (preferably pyridyl) or substituted(CH₂)_(m)-aryl wherein m is 0 (preferably methylphenyl). Thus preferredR⁴ groups include OH, OMe, O'Bu, OCH₂Ph, OCH₂CF₃, OC(O)(2-methylphenyl)and OC(O)(4-pyridyl); each of which is preferably substituted in the5-position or the 6-position.

[0154] In another preferred embodiment, R⁴ is selected from groups ofthe formula C(O)NR⁷R⁸ wherein R⁷ and R⁸ are each independently H,C₁₋₈alkyl, C₂₋₆alkenyl, SO₂C₁₋₆alkyl, (CH₂)_(m)—C₃₋₁₂cycloalkyl,(CH₂)_(m)-aryl, (CH₂)_(m)-heterocyclyl, (CH₂)_(m)-heterocyclylsubstituted by C₁₋₆alkyl (preferably methyl), (CH₂)_(m)-heteroaryl,wherein m=0, 1, 2 or 3, or may, together with the nitrogen atom to whichthey are bound, form a heterocyclyl group. Thus preferred R⁴ groupsinclude CONH₂ and

[0155] In another preferred embodiment, R⁴ is selected from groups ofthe formula

S(O)_(f)—(CH₂)_(e)—R³

[0156] wherein

[0157] e is 0 to 6;

[0158] R³ is hydrogen, halogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₁₂cycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxyl, cyano, nitro,trihalomethyl, phthalamido, C₆H₄NR⁷R⁸, C₆H₄(CH₂)NR⁷R⁸, C(O)R⁷,C(O)NR⁷R⁸, OC(o)R⁷, OC(O)NR⁷R⁸, CO₂R⁷, OCO₂R⁷, SO₂R⁷, SO₂NR⁷R⁸ orC(═NR⁷)NR⁷R⁸;

[0159] R⁷ and R⁸ are each independently H, C₁₋₈alkyl, C₂₋₆alkenyl,SO₂C₁₋₆alkyl, (CH₂)_(m)—C₃₋₁₂cycloalkyl, (CH₂)_(m)-aryl,(CH₂)_(m)-heterocyclyl, (CH₂)_(m)-heteroaryl, wherein m=0, 1 or 2, ormay, together with the nitrogen atom to which they are bound, form aheterocyclyl group.

[0160] A specific group pf componds of the invention are those offormula (Ia):

[0161] or a salt or solvate thereof or a physiologically functionalderivative thereof:

[0162] wherein

[0163] R¹ is a group of formula —NH—(CH₂)_(e)—R⁵ wherein either:

[0164] (i) e=2, 3 or 4; and R⁵ is NR⁷R⁸ wherein R⁷ and R⁸ are eachindependently selected from H, C₁₋₄alkyl, S(O)₂C₁₋₄alkyl,(CH₂)_(m)—C₃₋₈cycloalkyl, (CH₂)_(m)-aryl, (CH₂)_(m)-heterocyclyl, and(CH₂)_(m)-heteroaryl, wherein m=0, 1 or 2; or

[0165] (ii) e=2, 3 or 4; and R⁵ is NR⁷R⁸ wherein both R⁷ and R⁸ aretaken together with the N atom to which they are bonded to form aheterocyclyl group; or

[0166] (iii) e=1, 2 or 3; and R⁵ is a nitrogen-containing heteroaryl orheterocyclyl group which is bonded to the alkylene portion of R¹ by anatom other than nitrogen;

[0167] wherein any of said alkyl, cycloalkyl, aryl, heterocyclyl andheteroaryl groups may be optionally further substituted by one or twogroups selected from oxo, hydroxy, cyano, S(O)C₁₋₄alkyl, S(O)₂C₁₋₄alkyl,OC₁₋₄alkyl, C₁₋₄alkyl and NR⁹R¹⁰ wherein R⁹ and R¹⁰ are independentlyselected from H and C₁₋₄alkyl;

[0168] each R² is independently selected from hydrogen, CN, OC₁₋₄alkyl,halogen or trihalomethyl;

[0169] a is 1;

[0170] c is 1; and

[0171] R⁴ is selected from CN, halogen or trihalomethyl.

[0172] In a preferred embodiment of formula (Ia) R¹ is bonded to the2-position of the pyrimidine ring as those positions are shown below:

[0173] In another preferred embodiment of formula (Ia) R¹ is bonded tothe 4-position of the pyrimidine ring as those positions are shownabove.

[0174] In a preferred embodiment of formula (Ia), R¹ is a group offormula —NH—(CH₂)_(e)—R⁵ wherein e is 2, 3 or 4 and R⁵ is NR⁷R⁸ andwherein R⁷ and R⁸ are each independently selected from H, C₁₋₄alkyl,S(O)₂C₁₋₄alkyl, (CH₂)_(m)—C₃₋₈cycloalkyl, (CH₂)_(m)-aryl,(CH₂)_(m)-heterocyclyl, and (CH₂)_(m)-heteroaryl, wherein m is 0, 1 or2.

[0175] In a further preferred embodiment of formula (Ia), R¹ is a groupof formula —NH—(CH₂)_(e)—R⁵ wherein e is 2, 3 or 4, preferably 3, and R⁵is NR⁷R⁸ wherein R⁷ and R⁸ are each independently selected from H andC₄alkyl. More preferably R⁷ and R⁸ are each independently selected fromH, methyl, ethyl, n-propyl, isopropyl, and butyl. Most preferably R⁵ isrepresented by a group selected from any one of the following: amino,methylamino, dimethylamino, ethylamino, diethylamino, n-propylamino,di(n-propyl)amino, iso-propylamino, di(isopropyl)amino and butylamino.In a further embodiment, any of said C₁₋₄alkyl groups may be optionallysubstituted by one or two groups selected from, oxo, hydroxy, cyano,S(O)C₁₋₄alkyl, S(O)₂C₁₋₄alkyl, OC₁₋₄alkyl, C₁₋₄alkyl and NR⁹R¹⁰ whereinR⁹ and R¹⁰ are each independently selected from H and C₁₋₄alkyl. Apreferred substituent for said alkyl groups is C₁₋₄alkyl, morepreferably n-butyl. Thus R⁵ is preferably represented by the groupn-octylamino.

[0176] In a further preferred embodiment of formula (Ia), R¹ is a groupof formula —NH—(CH₂)_(e)—R⁵ wherein e is 2, 3 or 4, preferably 3, and R⁵is NR⁷R⁸ wherein either R⁷ or R⁸ is represented by the group(CH₂)_(m)—C₃₋₈cycloalkyl wherein m is 0, 1 or 2, preferably 0 or 1, morepreferably 0. More preferably, either R⁷ or R⁸ represent cyclopentyl orcyclohexyl. Most preferably R⁵ is represented by a group selected fromany one of the following: NH-cyclopentyl, NH—CH₂-cyclopentyl andNH-cyclohexyl. In a further embodiment, any of said C₃₋₈cycloalkylgroups may be optionally substituted by one or two groups selected from,oxo, hydroxy, cyano, S(O)C₁₋₄alkyl, S(O)₂C₁₋₄alkyl, OC₁₋₄alkyl,C₁₋₄alkyl and NR⁹R¹⁰ wherein R⁹ and R¹⁰ are each independently selectedfrom H and C₁₋₄alkyl. A preferred substituent for said alkyl groups isC₁₋₄alkyl, more preferably methyl. Thus R⁵ is preferably represented bythe group NH-(3-methylcyclopentyl).

[0177] In a further preferred embodiment of formula (Ia), R¹ is a groupof formula NH—(CH₂)_(e)—R⁵ wherein e is 2, 3 or 4, preferably 3, and R⁵is NR⁷R⁸ wherein either R⁷ or R⁸ is represented by the group(CH₂)_(m)-aryl wherein m is 0, 1 or 2, preferably 0 or 1. Morepreferably, R⁷ or R⁸ represent phenyl or benzyl. Most preferably R⁵ isrepresented by a group selected from any one of the following:N(Me)-phenyl and N(Me)-benzyl. In a further embodiment, any of said arylgroups may be optionally substituted by one or two groups selected from,oxo, hydroxy, cyano, S(O)C₁₋₄alkyl, S(O)₂C₁₋₄alkyl, OC₁₋₄alkyl,C₁₋₄alkyl and NR⁹R¹⁰ wherein R⁹ and R¹⁰ are each independently selectedfrom H and C₁₋₄alkyl.

[0178] In a further preferred embodiment of formula (Ia), R¹ is a groupof formula —NH—(CH₂)_(e)—R⁵ wherein e is 2, 3 or 4, preferably 3, and R⁵is NR⁷R⁸ wherein either R⁷ or R⁸ is represented by the group(CH₂)_(m)-heterocyclyl wherein m is 0, 1 or 2, preferably 0 or 2. Morepreferably R⁷ or R⁸ represent piperidine, piperazine, morpholine,tetrahydropyran or tetrahydrothiopyran. Most preferably R⁵ isrepresented by a group selected from any one of the following:

[0179] In a further embodiment, any of said heterocyclyl groups may beoptionally substituted by one or two groups selected from, oxo, hydroxy,cyano, S(O)C₁₋₄alkyl, S(O)₂C₁₋₄alkyl, OC₁₋₄alkyl, C₁₋₄alkyl and NR⁹R¹⁰wherein R⁹ and R¹⁰ are each independently selected from H and C₁₋₄alkyl.

[0180] In a further preferred embodiment of formula (Ia), R¹ is a groupof formula —NH—(CH₂)_(e)—R⁵ wherein e is 2, 3 or 4, preferably 3, and R⁵is NR⁷R⁸ wherein either R⁷ or R⁸ are represented by the group(CH₂)_(m)-heteroaryl wherein m is 0, 1 or 2, preferably 1. Morepreferably R⁷ or R⁸ represent furan, pyrrole, imidazole or pyridine.Most preferably R⁵ is represented by the group:

[0181] In a further embodiment of formula (Ia), any of said heteroarylgroups may be optionally substituted by one or two groups selected from,oxo, hydroxy, cyano, S(O)C₁₋₄alkyl, S(O)₂C₁₋₄alkyl, OC₁₋₄alkyl,C₁₋₄alkyl and NR⁹R¹⁰ wherein R⁹ and R¹⁰ are each independently selectedfrom H and C₁₋₄alkyl.

[0182] In a further preferred embodiment of formula (Ia), R¹ is a groupof formula —NH—(CH₂)_(e)—R⁵ wherein e is 2, 3 or 4, preferably 3, and R⁵is NR⁷R⁸ wherein either R⁷ or R⁸ are represented by the groupS(O)₂C₁₋₄alkyl. More preferably R⁷ or R⁸ represent S(O)₂Me. In a furtherembodiment, any of said C₁₋₄alkyl groups may be optionally substitutedby one or two groups selected from, oxo, hydroxy, cyano, S(O)C₁₋₄alkyl,S(O)₂C₁₋₄alkyl, OC₁₋₄alkyl, C₁₋₄alkyl and NR⁹R¹⁰ wherein R⁹ and R¹⁰ areeach independently selected from H and C₁₋₄alkyl.

[0183] In a preferred embodiment of formula (Ia), R¹ is a group offormula —NH—(CH₂)_(e)—R⁵ wherein e is 2, 3 or 4, preferably 2 or 3, morepreferably 3, and R⁵ is NR⁷R⁸ wherein both R⁷ and R⁸ are taken togetherwith the N atom to which they are bonded to form a heterocyclyl groupoptionally fused to a benzene ring. Preferably, said heterocyclyl groupis selected from piperidine, homopiperidine, piperazine, morpholine,pyrolidine and imidazolidine each of which may be optionally fused to abenzene ring. Most preferably R⁵ is represented by a group selected fromany one of the following:

[0184] In a further embodiment of formula (Ia), any of said heterocyclylgroups may be optionally substituted by one or two groups selected from,oxo, hydroxy, cyano, S(O)C₁₋₄alkyl, S(O)₂C₁₋₄alkyl, OC₁₋₄alkyl,C₁₋₄alkyl and NR⁹R¹⁰ wherein R⁹ and R¹⁰ are each independently selectedfrom H and C₁₋₄alkyl. Preferred substituents for said alkyl groups areoxo and C₁₋₄alkyl, more preferably methyl, ethyl, propyl or iso-propyl.Thus R⁵ is preferably represented by a group selected from any one ofthe following:

[0185] In a preferred embodiment of formula (Ia), R¹ is a group offormula —NH—(CH₂)_(n)—R⁵ wherein n is 1, 2 or 3, preferably 1 or 2, andR⁵ is a nitrogen-containing heteroaryl or heterocyclyl group which isbonded to the alkylene portion of R¹ by an atom other than nitrogen.Preferably R⁵ is a heterocyclyl group selected from piperidine,homopiperidine, piperazine, morpholine, pyrolidine and imidazolidine orR⁵ is a heteroaryl group selected from pyridine and imidazole. Mostpreferably R¹ is represented by a group selected from:

[0186] In a further embodiment of formula (Ia), any of said heteroarylor heterocyclyl groups may be optionally substituted by one or twogroups selected from, oxo, hydroxy, cyano, S(O)C₁₋₄alkyl,S(O)₂C₁₋₄alkyl, OC₁.₄alkyl, C₁₋₄alkyl and NR⁹R¹⁰ wherein R⁹ and R¹⁰ areeach independently selected from H and C₁₋₄alkyl.

[0187] In a preferred embodiment of formula (Ia) x is 1 or 2. In a morepreferred embodiment the R² substituent(s) are in the meta- and/orpara-position(s) relative to the bond to the pyrazolopyridine ringsystem. In a preferred embodiment, each R² is selected from chloro,fluoro and trifluoromethyl groups. In a more preferred embodiment,(R²)_(b) is represented by one or two substituents selected from F orCl. In a further preferred embodiment, (R²)_(b) is represented by a CF₃substituent. In a most preferred embodiment, (R²)_(b) and the phenylring to which such group(s) is/are bonded is selected from3-chloro-4-fluorophenyl, 3-chlorophenyl, 4-fluorophenyl and4-trifluoromethylphenyl. In an especially preferred embodiment, (R²)_(b)and the phenyl ring to which such group(s) is/are bonded is4-fluorophenyl.

[0188] In a preferred embodiment of formula (Ia), R⁴ is CF₃.

[0189] A specific group of compounds of formula (I) are those with theadditional proviso that when Z is N and R′ is in the 2-position of thepyrimidine ring it is not optionally substituted NH-phenyl.

[0190] Salts of the compounds of the present invention are alsoencompassed within the scope of the invention and may, for example,comprise acid addition salts resulting from reaction of an acid with anitrogen atom present in a compound of formula (I).

[0191] Salts encompassed within the term “pharmaceutically acceptablesalts” refer to non-toxic salts of the compounds of this invention.Representative salts include the following salts: Acetate,Benzenesulfonate, Benzoate, Bicarbonate, Bisulfate, Bitartrate, Borate,Bromide, Calcium Edetate, Camsylate, Carbonate, Chloride, Clavulanate,Citrate, Dihydrochloride, Edetate, Edisylate, Estolate, Esylate,Fumarate, Gluceptate, Gluconate, Glutamate, Glycollylarsanilate,Hexylresorcinate, Hydrabamine, Hydrobromide, Hydrochloride,Hydroxynaphthoate, Iodide, Isethionate, Lactate, Lactobionate, Laurate,Malate, Maleate, Mandelate, Mesylate, Methylbromide, Methylnitrate,Methylsulfate, Monopotassium Maleate, Mucate, Napsylate, Nitrate,N-methylglucamine, Oxalate, Pamoate (Embonate), Palmitate, Pantothenate,Phosphate/diphosphate, Polygalacturonate, Potassium, Salicylate, Sodium,Stearate, Subacetate, Succinate, Tannate, Tartrate, Teoclate, Tosylate,Triethiodide, Trimethylammonium and Valerate. Other salts which are notpharmaceutically acceptable may be useful in the preparation ofcompounds of this invention and these form a further aspect of theinvention.

[0192] Examples of compounds of the invention wherein Z is CH includethe following (Table 1): TABLE 1 Example # Compound name 12-(4-Fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridine 22-(4-Fluorophenyl)-6-methyl-3-(4-pyridinyl)pyrazolo[1,5-a]pyridine 32-(4-Fluorophenyl)-5-methyl-3-(4-pyridinyl)pyrazolo[1,5-a]pyridine 42-(4-Fluorophenyl)-4-methyl-3-(4-pyridinyl)pyrazolo[1,5-a]pyridine 52-(4-Fluorophenyl)-5-methoxy-3-(4-pyridinyl)pyrazolo[1,5-a]pyridine 62-(4-Fluorophenyl)-5-hydroxymethyl-3-(4-pyridinyl)pyrazolo[1,5-a]-pyridine 72-(4-Fluorophenyl)-4-hydroxymethyl-3-(4-pyridinyl)pyrazolo[1,5-a]-pyridine 86-Fluoro-2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridine 94-Fluoro-2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridine 10[2-(4-Fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridin-5-yl]methyl 2-methylbenzoate 11[2-(4-Fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridin-5-yl]methylisonicotinate 12[2-(4-Fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridin-5-yl]methylnicotinate 13[2-(4-Fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridin-5-yl]methyl 3-bromo-2-thiophenecarboxylate 14[2-(4-Fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridin-5-yl]methyl 6-aminonicotinate 15[2-(4-Fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridin-5-yl]methyl 5-(methylsulfonyl)-2-thiophenecarboxylate 16[2-(4-Fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridin-5-yl]methyl 2-aminonicotinate 17[2-(4-Fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridin-5-yl]methyl 3-(aminosulfonyl)-4-chlorobenzoate 18[2-(4-Fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridin-5-yl]methyl 3-methyl-2-thiophenecarboxylate 19[2-(4-Fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridin-5-yl]methyl 2-methoxybenzoate 20[2-(4-Fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridin-5-yl]methyl2,3-dichlorobenzoate 212-[2-(4-Fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridin-5-yl]-methyl-1H-isoindole-1,3(2H)-dione 22[2-(4-Fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridin-5-yl]-methanamine 232-(4-Fluorophenyl)-3-(4-pyridinyl)-6-(trifluoromethyl)pyrazolo[1,5-a]-pyridine 242-(4-Fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridin-5-ol 255-(n-Butoxy)-2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]-pyridine265-(Benzyloxy)-2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridine27 2-(4-Fluorophenyl)-3-(2-fluoro-4-pyridinyl)pyrazolo[1,5-a]pyridine 284-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-[2-(1H-imidazol-5-yl)ethyl]-2-pyridinamine 29N-Butyl-4-[2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyridinamine 303-(4-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyridinylamino)-1-propanol 31N-(4-chlorobenzyl)-4-[2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyridinamine 32N¹-4-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyridinyl-1,3-propanediamine 333-(2-Butoxy-4-pyridinyl)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine 344-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-hexyl-2-pyridinamine 35 4-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(4-methoxybenzyl)-2-pyridinamine 364-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-pentyl-2-pyridinamine 37 4-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-pyridinylmethyl)-2-pyridinamine 384-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propyl-2-pyridinamine 394-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-phenyl-2-pyridinamine 40N¹-4-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyridinyl-1,4-butanediamine 412-(4-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyridinylamino)-1-ethanol 42N-Benzyl-4-[2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyridinamine 434-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-dimethyl-2-pyridinamine 443-(2,6-Difluoro-4-pyridinyl)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine45N-Benzyl-6-fluoro-4-[2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyridinamine 46 2-(4-Fluorophenyl)-3-(2-fluoro-4-pyridinyl)-6-trifluoromethylpyrazolo[1,5-a]pyridine 474-[2-(4-Fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridin-3-yl]-N-isopropyl-2-pyridinamine 48N-Cyclopropyl-4-[2-(4-fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridin-3-yl]-2-pyridinamine 493-(4-[2-(4-Fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridin-3-yl]-2-pyridinylamino)-1-propanol 506-Bromo-2-(4-fluorophenyl)-3-(2-fluoro-4-pyridinyl)pyrazolo[1,5-a]-pyridine51 N-(3-Aminopropyl)-4-[6-bromo-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyridinamine 526-Cyano-2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridine 532-(4-Fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridine-6- carboxamide54 6-Cyano-2-(4-fluorophenyl)-3-(2-fluoro-4-pyridinyl)pyrazolo[1,5-a]pyridine 556-Cyano-4-[2-(4-fluorophenyl)-pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropyl-2-pyridinamine

[0193] Examples of compounds of the invention wherein Z is N include thefollowing (Table 2): TABLE 2 Example # Compound name 562-(4-Fluorophenyl)-3-(4-pyrimidinyl)-pyrazolo[1,5-a]pyridine 572-(4-Fluorophenyl)-3-(4-(2-methylthio)pyrimidinyl)-pyrazolo[1,5-a]pyridine 582-(4-Fluorophenyl)-3-(4-(2-methylsulfinyl)pyrimidinyl)-pyrazolo[1,5-a]pyridine59 2-(4-Fluorophenyl)-3-(4-(2-methylsulfonyl)pyrimidinyl)-pyrazolo[1,5-a]pyridine 60N-Butyl-4-[2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine 61N-Cyclopropyl-4-[2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine 62N-Benzyl-4-[2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine 634-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(2-propyl)-2-pyrimidinamine 644-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine 654-[2-(4-Fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine 66N-Butyl-4-[2-(4-fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine 67N-Benzyl-4-[2-(4-fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine 68N-Cyclopropyl-4-[2-(4-fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine 694-[2-(4-Fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridin-3-yl]-N-(2-propyl)-2-pyrimidinamine 704-[2-(4-Fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridin-3-yl]-N-(2-propenyl)-2-pyrimidinamine 714-[2-(4-Fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridin-3-yl]-N-(2,2,2-trifluoroethyl)-2-pyrimidinamine 723-(4-[2-(4-Fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinylamino)-1-propanol 73N-Cyclopropyl-4-[6-cyano-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine 74N-Cyclopropyl-4-[6-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine 752-(4-Fluorophenyl)-3-(4-(2-cyclopropylamino)pyrimidinyl)-6-pyrazolo[1,5-a]pyridinylcarboxamide 762-(4-Fluorophenyl)-3-(4-(2-(3-hydroxypropyl)amino)pyrimidinyl)-6-pyrazolo[1,5-a]pyridinylcarboxamide 772-(4-Fluorophenyl)-3-(4-(2-methylthio)pyrimidinyl)-6-trifluoromethylpyrazolo-[1,5-a]pyridine 782-(4-Fluorophenyl)-3-(4-(2-methylsulfonyl)pyrimidinyl)-6-trifluoromethylpyrazolo-[1,5-a]pyridine 792-(4-Fluorophenyl)-3-(4-(2-(3-(4-methylpiperazino)propyl)amino)pyrimidinyl)-6-pyrazolo-[1,5-a]pyridinylcarboxamide 804-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-[2-(1H-imidazol-5-yl)ethyl]-2-pyrimidinamine 814-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-pyridinyl-methyl)-2-pyrimidinamine 824-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(2-pyridinylmethyl)-2-pyrimidinamine 834-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(4-pyridinyl-methyl)-2-pyrimidinamine 84 2-(4-Fluorophenyl)-3-(2-phenoxypyrimidin-4-yl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridine 853-({4-[2-(4-Fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}oxy)-N,N-dimethylaniline 863-[2-(2,5-Dimethylphenoxy)pyrimidin-4-yl]-2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridine

[0194] Examples of compounds of formula (Ia) include the following(Table 3) as well as salts or solvates thereof, particularlypharmaceutically acceptable salts or solvates thereof, orphysiologically functional derivatives thereof: TABLE 3 Example #Compound name 87 N-[3-(dimethylamino)propyl]-N-[4-{2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl}pyrimidin-2-yl]amine 88N-[3-(dimethylamino)propyl]-N-[4-{6-(trifluoromethyl)-2-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyridin-3-yl}pyrimidin-2-yl]amine89 N-[4-{2-[3-chloro-4-fluorophenyl]-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl}pyrimidin-2-yl]-N-[3-(dimethylamino)propyl]amine 90N-{4-[2-(3-chlorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-[3-(dimethylamino)propyl]amine 91N-{4-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-[2-(dimethylamino)ethyl]amine 92N-[4-(diethylamino)butyl]-N-(4-{6-(trifluoromethyl)-2-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyridin-3-yl}pyrimidin-2-yl)amine 93N-{4-[2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-[4-(diethylamino)butyl]amine 94N-{4-[2-(3-chlorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-[4-(diethylamino)butyl]amine 95N-[2-(diethylamino)ethyl]-N-(4-{6-(trifluoromethyl)-2-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyridin-3-yl}pyrimidin-2-yl)amine 96N-{4-[2-(3-chlorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-[2-(diethylamino)ethyl]amine 97N-[2-(dipropylamino)ethyl]-N-(4-{6-(trifluoromethyl)-2-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyridin-3-yl}pyrimidin-2-yl)amine 98N-{4-[2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-[2-(dipropylamino)ethyl]amine 99N-{4-[2-(3-chlorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-[2-(dipropylamino)ethyl]amine 100N-{4-[2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-[2-(diisopropylamino)ethyl]amine 101N-{4-[2-(3-chlorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-[2-(diisopropylamino)ethyl]amine 102N-{4-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-(2-pyrrolidin-1-ylethyl)amine 103N-(2-pyrrolidin-1-ylethyl)-N-(4-{6-(trifluoromethyl)-2-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyridin-3-yl}pyrimidin-2-yl)amine 104N-{4-[2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-(2-pyrrolidin-1-ylethyl)amine 105N-{4-[2-(3-chlorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-(2-pyrrolidin-1-ylethyl)amine 106N-{4-[2-(3-chlorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-(4-pyrrolidin-1-ylbutyl)amine 107N-{4-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-(2-piperidin-1-ylethyl)amine 108N-(2-piperidin-1-ylethyl)-N-(4-{6-(trifluoromethyl)-2-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyridin-3-yl}pyrimidin-2-yl)amine 109N-{4-[2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-(2-piperidin-1-ylethyl)amine 110N-{4-[2-(3-chlorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-(2-piperidin-1-ylethyl)amin 111N-{4-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-(2-piperidin-1-ylpropyl)amine 112N-(3-piperidin-1-ylpropyl)-N-(4-{6-(trifluoromethyl)-2-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyridin-3-yl}pyrimidin-2-yl)amine 113N-{4-[2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-(3-piperidin-1-ylpropyl)amine 114N-{4-[2-(3-chlorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-(3-piperidin-1-ylpropyl)amine 115N-(2-azepan-1-ylethyl)-N-(4-{6-(trifluoromethyl)-2-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyridin-3-yl}pyrimidin-2-yl)amine 116N-(2-azepan-1-ylethyl)-N-{4-[2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}amine 117N-(2-azepan-1-ylethyl)-N-{4-[2-(3-chlorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}amine 118N-{4-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-(2-morpholin-4-ylethyl)amine 119N-(2-morpholin-4-ylethyl)-N-(4-{6-(trifluoromethyl)-2-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyridin-3-yl}pyrimidin-2-yl)amine 120N-{4-[2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-(2-morpholin-4-ylethyl)amine 121N-(3-morpholin-4-ylpropyl)-N-(4-{6-(trifluoromethyl)-2-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyridin-3-yl}pyrimidin-2-yl)amine 122N-{4-[2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-(3-morpholin-4-ylpropyl)amine 123N-{4-[2-(3-chlorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-(3-morpholin-4-ylpropyl)amine 124N-{4-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-[3-(4-methylpiperazin-1-yl)propyl]amine 125N-{4-[2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]-pyridin-3-yl]pyrimidin-2-yl}-N-[3-(4-methylpiperazin-1-yl)propyl]amine126N-{4-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-[2-(4-methylpiperazin-1-yl)ethyl]amine 127N-[2-(4-propylpiperazin-1-yl)ethyl]-N-(4-{6-(trifluoromethyl)-2-[4-trifluoromethyl)phenyl]pyrazolo[1,5-a]pyridin-3-yl}pyrimidin-2-yl)amine 128N-{4-[2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-[2-(4-propylpiperazin-1-yl)ethyl]amine129N-{4-[2-(3-chlorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-[2-(4-propylpiperazin-1-yl)ethyl]amine

[0195] Examples of preferred compounds of formula (Ia) include thefollowing (Table 4) as well as salts or solvates thereof, particularlypharmaceutically acceptable salts or solvates thereof, orphysiologically functional derivatives thereof: TABLE 4 Example #Compound name 89N-[4-{2-[3-chloro-4-fluorophenyl]-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl}pyrimidin-2-yl]-N-[3-(dimethylamino)propyl]amine 90N-{4-[2-(3-chlorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-[3-(dimethylamino)propyl]amine 93N-{4-[2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-[4-(diethylamino)butyl]amine 94N-{4-[2-(3-chlorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-[4-(diethylamino)butyl]amine 96N-{4-[2-(3-chlorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-[2-(diethylamino)ethyl]amine 98N-{4-[2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-[2-(dipropylamino)ethyl]amine 100N-{4-[2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-[2-(diisopropylamino)ethyl]amine 106N-{4-[2-(3-chlorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-(4-pyrrolidin-1-ylbutyl)amine 113N-{4-[2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-(3-piperidin-1-ylpropyl)amine 117N-(2-azepan-1-ylethyl)-N-{4-[2-(3-chlorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}amine 120N-{4-[2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-(2-morpholin-4-ylethyl)amine 122N-{4-[2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-(3-morpholin-4-ylpropyl)amine 123N-{4-[2-(3-chlorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-(3-morpholin-4-ylpropyl)amine 124N-{4-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-[3-(4-methylpiperazin-1-yl)propyl]amine 125N-{4-[2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]-pyridin-3-yl]pyrimidin-2-yl}-N-[3-(4-methylpiperazin-1-yl)propyl]amine128 N-{4-[2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-[2-(4-propylpiperazin-1-yl)ethyl]amine129N-{4-[2-(3-chlorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-[2-(4-propylpiperazin-1-yl)ethyl]amine

[0196] Examples of particularly preferred compounds of formula (Ia)include the following (Table 5) as well as salts or solvates thereof,particularly pharmaceutically acceptable salts or solvates thereof, orphysiologically functional derivatives thereof: TABLE 5 Example #Compound name 93 N-{4-[2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5- a]pyridin-3-yl]pyrimidin-2-yl}-N-[4-(diethylamino)butyl]amine 94 N-{4-[2-(3-chlorophenyl)-6-(trifluoromethyl)pyrazolo[1,5- a]pyridin-3-yl]pyrimidin-2-yl}-N-[4-(diethylamino)butyl]amine 106 N-{4-[2-(3-chlorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-(4-pyrrolidin- 1-ylbutyl)amine 123N-{4-[2-(3-chlorophenyl)-6- (trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-(3-morpholin-4- ylpropyl)amine 124N-{4-[2-(4-fluorophenyl)-6- (trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-[3-(4-methylpiperazin-1-yl)propyl]amine 125N-{4-[2-(3-chloro-4-fluorophenyl)-6- (trifluoromethyl)pyrazolo[1,5-a]-pyridin-3-yl]pyrimidin-2-yl}-N-[3-(4-methylpiperazin-1-yl)propyl]amine 128 N-{4-[2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-[2-(4-propylpiperazin-1- yl)ethyl]amine129 N-{4-[2-(3-chlorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-[2-(4-propylpiperazin-1- yl)ethyl]amine

[0197] S particularly prefferred compound of formula (I) is3-(4-[2-(4-fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinylamino)-1-propanol.

[0198] The compounds of this invention may be made by a variety ofmethods, including standard chemistry. Any previously defined variablewill continue to have the previously defined meaning unless otherwiseindicated. Illustrative general synthetic methods are set out below andthen specific compounds of the invention are prepared in the workingExamples.

[0199] For example, a general method (A) for preparing the compounds ofFormula (I) comprises the reaction of a compound of Formula (VII)

[0200] with a compound of general Formula (VIII) or (IX)

[0201] wherein Z is CH or N and Y is methyl or butyl.

[0202] This general method (A) can be conveniently performed by mixingthe two compounds in an inert solvent, in the presence of a palladiumcatalyst, and optionally heating the mixture to about 100° C. Preferablythe reaction is performed using an approximately equimolar mixture of(VII) and (VIII), or an approximately equimolar mixture of (VII) and(IX). The palladium catalyst is preferably present in the proportion of1-5 mol % compared to (VII). Palladium catalysts which may be usedinclude, but are not limited to, tetrakistriphenylphosphinepalladium(0), bis(triphenylphosphine)palladium dichloride. When one ofthe reactant partners is a compound of general formula (IX), thereaction is more conveniently carried out by adding a base in aproportion equivalent to, or greater than, that of (IX). Preferably thebase is a trialkylamine or sodium hydrogen carbonate.

[0203] Another general method (B) for the preparation of the compoundsof this invention is the reaction of a compound of Formula (VII) with acompound of Formula (X) as summarized below to give compounds of Formula(I) where R¹ is hydrogen.

[0204] The type of reaction utilized in general method (B) is welldocumented in the literature and is routinely referred to as a ‘Stille’coupling (Stille, Angew. Chem. Int. Ed. Engl. 1986, 25, 508). Thisreaction is brought about by mixing the two reactants in an inertsolvent in the presence of a catalytic quantity of a palladium speciesand heating the reaction mixture. Conveniently the solvent is, forexample, toluene, dioxane, tetrahydrofuran or dimethylformamide and thepalladium catalyst is a palladium(0) species, or a convenient precursorthereof, for example, tetrakis(triphenylphosphine)palladium(0) orbis(triphenylphosphine) palladium dichloride. For example, when R⁴ ishydrogen, the reaction is most conveniently performed by mixing the tworeactants, in an approximate equimolar ratio, in toluene, adding anamount of tetrakis(triphenylphosphine)palladium(0) equal to about 5 mol% of that of (VII), and heating the mixture at about 100-120° C. untilthe reaction is judged complete by the disappearance of either (VII) or(X). Typically this reaction requires between 12 and 48 h to proceed tocompletion. The product can be conveniently isolated using procedurestypical for this Stille coupling procedure.

[0205] One skilled in the art will recognize that a similar reaction,illustrated below in general method (C) can be used to prepare compoundsof the invention using boron containing reactants such as (XII).

[0206] The use of boronic acids, or esters, in such a coupling reactionis typically referred to as a ‘Suzuki’ coupling reaction (Suzuki, A. etal. Synth. Commun. 1981, 11, 513). Said reaction is conveniently broughtabout by mixing the two reactants, in an inert solvent, in the presenceof a catalytic quantity of a palladium species and a base, and heatingthe reaction mixture. Conveniently the solvent is, for example, toluene,dioxane, tetrahydrofuran or dimethylformamide and the palladium catalystis a palladium(0) species, or a convenient precursor thereof, forexample, tetrakis(triphenylphosphine) palladium(0) orbis(triphenylphosphine)palladium dichloride, and the base is sodiumbicarbonate or a trialkyl amine such as triethyl amine.

[0207] Boron containing compounds such as (XII) and tin containingcompounds such as (X) are either commercially available or can beprepared using methods known to one skilled in the art (Stille, Angew.Chem. Int. Ed. Engl. 1986, 25, 508; Snieckus, V. et al. J. Org. Chem.1995, 60, 292-6).

[0208] Compounds of general formula (VII) may be conveniently preparedfrom compounds of Formula (XII) by a decarboxylation/brominationsequence as shown below.

[0209] This reaction can be achieved by treatment of a compound ofgeneral formula (XII), dissolved in a suitable solvent, with a basefollowed by a brominating agent and stirring the mixture at, or about,25° C. until the reaction is judged complete by the disappearance of(XII). Suitable solvents include, but are not limited to,dimethylformamide, dimethylacetamide, dioxane and the like. Convenientlythe base is sodium hydrogen carbonate and the brominating agent can be,for example, N-bromosuccinimide. Alternatively, compounds of generalformula (VII) can be conveniently prepared by treatment of a compound ofgeneral formula (XIII) with a brominating agent as summarized below.

[0210] This reaction can be easily carried out by dissolving thecompound of general formula (XIII) in an inert solvent and adding to thesolution a brominating agent in sufficient quantity to effect completereaction of (XIII). Preferably the solvent is dimethylformamide,dimethylacetamide, dioxane and the like and brominating agents include,but are not limited to, bromine, N-bromosuccinimide, N-bromoacetamideand the like.

[0211] Compounds of general formula (XIII) may be conveniently preparedby the decarboxylation of a compound of general formula (XII) assummarized below.

[0212] Said decarboxylation may be carried out by any one of a varietyof methods described in the literature for similar decarboxylations. Forexample: heating a solution of a compound of general formula (XII) in aninert solvent, or conversion to a ‘Barton ester’ followed by treatmentwith a radical reductant, for example tributyltin hydride (Crich, D.Aldrichimica Acta, 1987, 20, 35).

[0213] Compounds of general formula (XII) can be prepared most readilyby simple hydrolysis of lower alkyl esters of general formula (XIV).Esters such as (XIV) are commonly referred to aspyrazolo[1,5-a]pyridines (Hardy, C. R. Adv. Het. Chem. 1984, 36, 343)and may be prepared by a cycloaddition reaction between compounds ofgeneral formula (XV) and acetylenes of general formula (XVI), assummarized below.

[0214] Cycloaddition reactions such as these are commonly known as [3+2]dipolar cycloaddition reactions. Conveniently the reaction may becarried out by mixing the reactants (XV) and (XVI), in equimolaramounts, in an inert solvent and adding a suitable base. The mixture isthen stirred at between 20-100° C. until the reaction is judged completeby the disappearance of one of the reactants. Preferred solvents includebut are not limited to acetonitrile, dioxane, tetrahydrofuran,dimethylformamide and the like. Preferred bases include non-nucleophilicamines such as 1,8-diazabicyclo[5.4.0]undec-7-ene,1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane and thelike.

[0215] Esters such as those of Formula (XIV) can be convenientlyhydrolyzed to their corresponding carboxylic acids by standardhydrolysis conditions employed to effect similar hydrolysis reactions(Larock, Comprehensive Organic Transformations, 1989, 981). For example,treatment of a solution of a compound of general formula (XIV) in alower alcohol, for example methanol, with sodium hydroxide followed byheating the mixture for an appropriate time gives the compound ofgeneral formula (XII).

[0216] Compounds of general formula (XV) are aminated pyridinederivatives and are either commercially available or can be convenientlyprepared by reacting a suitable pyridine with an aminating reagent suchas O-(mesitylsulfonyl)hydroxylamine, O-(diphenylphosphinyl)hydroxylamineand the like.

[0217] Acetylenic esters such as those of general formula (XVI) areeither known compounds or can be prepared by methods described in theliterature. Preferred methods include the reaction of acetylenes such asthose of general formula (XVII) with a suitable base to generate anacetylenic anion and subsequent reaction of the anion with analkoxycarbonylating agent, as summarized below.

[0218] Preferably the acetylene (XVII) is dissolved in an inert solvent,such as tetrahydrofuran, and the solution is cooled to about −75° C. Anon-nuclephilic base is added in sufficient quantity to effectdeprotonation of the acetylene (XVII). The preferred bases include, butare not limited to, n-butyllithium, lithium diisopropylamide, sodiumbis(trimethylsilyl)amide and the like. To the reaction mixture is thenadded a reagent capable of reacting with an anion to introduce analkoxycarbonyl group. Preferred reagents include, but are not limitedto, methyl chloroformate, ethyl chloroformate, benzyl chloroformate andthe like.

[0219] Arylalkynes such as (XVII) are either known compounds or can beprepared by literature methods such as those described in, for example,Negishi, E. J. Org. Chem. 1997, 62, 8957.

[0220] Compounds of general formula (XIII) can also be prepared via anumber of other convenient routes. Disubstituted acetylenes asrepresented by formula (XVIII) can be treated with an aminating agent,optionally in the presence of a base, to give compounds of generalformula (XIII). The aminating agent is, preferably,O-(mesitylsulfonyl)hydroxylamine and the base is potassium carbonate.

[0221] Disubstituted acetylenes such as (XVIII) are readily prepared bya palladium catalyzed coupling reaction between aryl acetylenes and2-halopyridines using methods described in the literature (Yamanake et.al, Chem. Pharm. Bull. 1988, 1890).

[0222] An alternative synthesis of compounds of general formula (XIII)involves treating a ketone of general formula (XIX) with an aminatingagent in a suitable solvent and optionally heating the reaction. Theaminating agent is, preferably, O-(mesitylsulfonyl)hydroxylamine andpreferred solvents include chloroform, dichloromethane and the like.

[0223] Ketones such as those of general formula (XIX) can be readilyprepared using procedures described in the literature (Cassity, R. P.;Taylor, L. T.; Wolfe, J. F. J. Org. Chem. 1978, 2286). A more preferredapproach to compounds of general formula (XII) involves the conversionof ketones of general formula (XIX) to oximes such as (XX) followed bytreatment of said oximes with an aminating agent. Typically, oximes ofgeneral formula (XX) are readily prepared by treating ketones of generalformula (XIX) with a source of hydroxylamine, in an appropriate solvent,and optionally in the presence of a base. Preferably the source ofhydroxylamine is hydroxylamine hydrochloride and the base is sodiumcarbonate, potassium carbonate, or an aqueous solution of sodiumhydroxide. Preferred solvents include lower alcohols, such as methanoland ethanol, or acetonitrile. The aminating agent is, preferably,O-(mesitylsulfonyl)hydroxylamine and preferred solvents includechloroform, dichloromethane and the like.

[0224] A still more preferred method for the preparation of compounds ofgeneral formula (XIII) from oximes of general formula (XX) involves thetreatment of the said oximes with an acylating or sulfonylating agent inthe presence of a base to generate azirines of general formula (XXI).Azirines such as (XXI) can be rearranged to compounds of general formula(XIII) by heating a solution of said azirine in a suitable solvent attemperatures of about −100-180° C. More preferably the rearrangement iscarried out in the presence of FeCl₂. In the presence of FeCl₂ therearrangement occurs at lower temperatures and in a higher yield.Typically the azirines (XXI) can be prepared by treatment of oximes ofgeneral formula (XX) with acetic anhydride, trifluoroacetic anhydride,methanesulfonyl chloride, toluenesulfonyl chloride and the like in aninert solvent, for example, chloroform, dichloromethane or toluene.Preferred bases include, but are not limited to, triethylamine,diisopropylethylamine, pyridine and the like.

[0225] A general method (D) for the preparation of compounds of generalformula (V) comprises the reaction of a compound of formula (XXII) witha compound of general formula (XXIII).

[0226] wherein Q is alkyloxy, alkylthio or dialkylamino.

[0227] The general method (D) can be readily carried out by mixing acompound of general formula (XXII) with a compound of general formula(XXIII) in a suitable solvent, optionally in the presence of a base, andheating the reaction mixture to about 50-150° C. Typically the solventis a lower alcohol such as methanol, ethanol, isopropanol and the like,and the base can be, for example, a sodium alkoxide, potassium carbonateor an amine base such as triethylamine.

[0228] Compounds of general formula (XXII) may be conveniently preparedby reacting a compound of general formula (XXIV) with adimethylformamide dialkylacetal, to give compounds of formula (XXII)wherein Q is Me₂N, or with a trialkyl orthoformate or a dialkoxymethylacetate, to give compounds of formula (XXII) wherein Q is an alkoxygroup. Conveniently, a dimethylformamide dialkylacetal isdimethylformamide dimethyl acetal or dimethylformamide di-tertbutylacetal and the reaction carried out by mixing the compound of generalformula (XXIV) with the dimethylformamide dialkylacetal and optionallyheating the reaction. Preferred trialkyl orthoformates include trimethylorthoformate and triethyl orthoformate. In a similar manner,diethoxymethyl acetate can be employed to prepare compounds of generalformula (XXII) wherein Q is EtO—.

[0229] Compounds of general formula (XXIV) can be prepared fromcompounds of formula (XIII) by an acylation procedure. Typically theacylation is conveniently carried out by treating the compounds offormula (XIII) with an acylating agent optionally in the presence of anacid catalyst. The preferred acylating agent is acetic anhydride and aconvenient acid is sulfuric acid.

[0230] Methods for the synthesis of compounds of formula (XIII) aredescribed above.

[0231] Certain compounds of general formula (V) may be convenientlyprepared by a process which involves reacting a ketone of generalformula (XXV) with an N-aminopyridine derivative in the presence of anacid or a base. Typically the acid is p-toluenesulfonic acid and thebase can be potassium carbonate, sodium hydroxide, caesium carbonate,lithium hydroxide, triethylamine, potassium tert-butoxide.

[0232] Compounds of general formula (I) can also be converted toalternate compounds of general formula (I).

[0233] Compounds of general formula (I) wherein R¹ is a leaving group,for example a halogen such as chloride, or a sulfone such asmethanesulfonyl can be converted into compounds of general formula (I)wherein R¹ is an ether or an amino group by treatment of said chloro, ormethanesulfonyl derivative with alcohols or amines. Thus, a particularlypreferred method for synthesising compounds of general formula (V)wherein R¹ is —NH—(CH₂)_(e)—R⁵ is shown below. A compound of generalformula (XXVI) is mixed at room temperature with a neat amine of generalformula H₂N—(CH₂)_(e)—R₅. The mixture is then heated with an airgununtil a homogenoeous melt is obtained. This usually takes about 0.2minutes. Upon cooling, water is added and the compound of generalformula (I) precipates out and may be separated by filtration.

[0234] Compounds of general formula (XXVI) may be produced by thereaction of oxone with compounds of general formula (XXVII) as shownbelow.

[0235] Compounds of general formula (XXVII) may be produced by reactionof a compound of formula (VII) with a compound of formula (VIII) whereinZ is N, R¹ is —SMe and Y is butyl. The synthesis of a compound offormula (VIII) wherein Z is N, R¹ is —SMe and Y is butyl is described inthe literature (Sandosham, J. and Undheim, K. Tetrahedron 1994, 50, 275;Majeed, A. J. et al Tetrahedron 1989, 45, 993).

[0236] Compounds of general formula (I), wherein R⁴ is hydrogen can beconverted into compounds wherein R⁴ is bromide or iodide and is attachedto position 6. Said conversion is conveniently carried out by additionof a brominating agent such as N-bromosuccinimide, or an iodinatingagent such as N-iodosuccinimide, to a solution of a compound of generalformula (XXX) in an appropriate solvent. Preferred solvents includedimethylformamide, dichloromethane and the like.

[0237] Compounds of general formula (I), wherein R⁴ is a bromide oriodide and is attached to position 6 can be converted to compounds withdifferent substitutions at position 6 by a variety of methods. Forexample, treatment of a compound of general formula (XXXI), wherein R⁴is bromide or iodide, under conditions well known in the art as Stillecoupling reactions or Suzuki coupling reactions leads to compoundswherein R⁴ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyano,carboalkoxy, or alkylamino.

[0238] Compounds of general formula (XXXI) wherein R⁴ is atrifluoromethyl group (CF₃) can be converted into compounds wherein R⁴is a carboxylic acid derivative. Preferably said transformation iscarried out by treatment of a compound of general formula (XXXII) with asuitable base in an alcoholic solvent and optionally heating thereaction to about 80° C. Preferably the base is a sodium or potassiumalkoxide such as sodium ethoxide and the like and the preferred solventsinclude, but are not limited to, methanol, ethanol, propanol,isopropanol and the like. The resulting trialkylorthoesters can beconverted to lower alkyl esters by treatment of said orthoesters in asuitable solvent with an acid in the presence of water. Preferred acidsinclude p-toluenesulfonic acid, hydrochloric acid and sulfuric acid andthe preferred solvents include lower alcohols and acetone. Lower alkylesters such as those represented by general formula (XXXIII) can befurther converted into different compounds by transformation of theester group in a manner well known in the art.

[0239] Compounds of general formula (I), wherein R¹, R² or R⁴ contains ahydroxyl group can be reacted to give compounds wherein the hydroxylgroup is converted to an ester, carbonate or carbamate group usingprocedures well known in the literature (March J. Advanced OrganicChemistry).

[0240] Similarly, compounds of general formula (I), wherein R¹, R² or R⁴contains an amino group can be reacted to give compounds wherein theamino group is converted to an amide, carbamate or urea group usingprocedures known in the literature (March J. Advanced OrganicChemistry).

[0241] Certain compounds of formula (I) wherein at least one R² group issubstituted on an ortho position of the phenyl ring may be prepared bythe reaction of a compound of formula (XXXIV) wherein Y is methyl orbutyl and wherein at least one R² group is substituted on an orthoposition of the phenyl ring:

[0242] with a compound of formula (XXXV):

[0243] This reaction is essentially the reverse of the coupling reactiondescribed above between compounds of formula (VIII) and (IX). Thereaction conditions are analogous to those previously described for thecoupling reaction between compounds of formula (VIII) and (IX).

[0244] Compound (XXXIV) wherein Y is butyl may be prepared from acompound of formula (VII) using a strong base, butyl lithium andtri-n-butyl stannyl chloride at low temperature (e.g. −78° C.) in aninert solvent such as THF.

[0245] The present invention includes within its scope a process for thepreparation of a compound of the invention which process comprises thestep of mixing a compound of general formula (XIX)

[0246] wherein x, R² and R⁴ are as defined for formula (I) above, withan amine of general formula H₂N—(CH₂)_(n)—R⁵ wherein R⁵ is as definedfor formula (I) above, and heating to form a homogeneous melt.

[0247] The present invention also includes within its scope a compoundof general formula (XIX)

[0248] wherein x is 1, 2 or 3; and each R² is independently selectedfrom hydrogen, CN, OC₁₋₄alkyl, halogen or trihalomethyl; and

[0249] R⁴ is selected from CN, halogen or trihalomethyl,

[0250] for use as an intermediate in the synthesis of a compound offormula (I) or a salt or solvate thereof or a physiologically functionalderivative thereof.

[0251] The present invention also includes within its scope a compoundof general formula (XX)

[0252] wherein x is 1, 2 or 3; and each R² is independently selectedfrom hydrogen, CN, OC₁₋₄alkyl, halogen or trihalomethyl; and

[0253] R⁴ is selected from CN, halogen or trihalomethyl,

[0254] for use as an intermediate in the synthesis of a compound offormula (I) or a salt or solvate thereof or a physiologically functionalderivative thereof.

[0255] Examples of compounds of general formula (XIX) and (XX) which areincluded within the scope of the present invention as usefulintermediates for the preparation of a compound of formula (I) or a saltor solvate thereof or a physiologically functional derivative thereofinclude the following:

[0256] 4-[2-(4-Fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl methyl sulfide;

[0257] Methyl4-{6-(trifluoromethyl)-2-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyridin-3-yl}pyrimidin-2-ylsulfide;

[0258]4-[2-(3-Chloro-4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-ylmethyl sulfide;

[0259] Methyl 4-{6-(trifluoromethyl)-2-[3-chlorophenyl]pyrazolo[1,5-a]pyridin-3-yl}pyrimidin-2-yl sulfide;

[0260]4-[2-(4-Fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-ylmethyl sulfone;

[0261] Methyl4-{6-(trifluoromethyl)-2-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyridin-3-yl}pyrimidin-2-ylsulfone;

[0262] Methyl4-{6-(trifluoromethyl)-2-[3-chlorophenyl]pyrazolo[1,5-a]pyridin-3-yl}pyrimidin-2-ylsulfone; and

[0263] Methyl4-{6-(trifluoromethyl)-2-[3-chlorophenyl]pyrazolo[1,5-a]pyridin-3-yl}pyrimidin-2-ylsulfone.

[0264] Whilst it is possible for the compounds, salts, solvates orphysiologically functional derivatives of the present invention to beadministered as the new chemical, the compounds of Formula (I) and theirpharmaceutically acceptable derivatives are conveniently administered inthe form of pharmaceutical compositions. Thus, in another aspect of theinvention, we provide a pharmaceutical composition comprising a compoundof formula (1) or a pharmaceutically acceptable derivative thereofadapted for use in human or veterinary medicine. Such compositions mayconveniently be presented for use in conventional manner in admixturewith one or more physiologically acceptable carriers or excipients.

[0265] The compounds of Formula (I) and their pharmaceuticallyacceptable derivatives may be formulated for administration in anysuitable manner. They may, for example, be formulated for topicaladministration or administration by inhalation or, more preferably, fororal, transdermal or parenteral administration. The pharmaceuticalcomposition may be in a form such that it can effect controlled releaseof the compounds of Formula (I) and their pharmaceutically acceptablederivatives. A particularly preferred method of administration, andcorresponding formulation, is oral administration.

[0266] For oral administration, the pharmaceutical composition may takethe form of, and be administered as, for example, tablets (includingsub-lingual tablets) and capsules (each including timed release andsustained release formulations), pills, powders, granules, elixirs,tinctures, emulsions, solutions, syrups or suspensions prepared byconventional means with acceptable excipients.

[0267] For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Powders are prepared by comminuting thecompound to a suitable fine size and mixing with a similarly comminutedpharmaceutical carrier such as an edible carbohydrate, as, for example,starch or mannitol. Flavoring, preservative, dispersing and coloringagent can also be present.

[0268] Capsules can be made by preparing a powder mixture as describedabove, and filling formed gelatin sheaths. Glidants and lubricants suchas colloidal silica, talc, magnesium stearate, calcium stearate or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar-agar, calcium carbonate or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

[0269] Moreover, when desired or necessary, suitable binders,lubricants, disintegrating agents and coloring agents can also beincorporated into the mixture. Suitable binders include starch, gelatin,natural sugars such as glucose or -beta-lactose, corn sweeteners,natural and synthetic gums such as acacia, tragacanth or sodiumalginate, carboxymethylcellulose, polyethylene glycol, waxes and thelike. Lubricants used in these dosage forms include sodium oleate,sodium stearate, magnesium stearate, sodium benzoate, sodium acetate,sodium chloride and the like. Disintegrators include, withoutlimitation, starch, methyl cellulose, agar, bentonite, xanthan gum andthe like. Tablets are formulated, for example, by preparing a powdermixture, granulating or slugging, adding a lubricant and disintegrantand pressing into tablets. A powder mixture is prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove, and optionally, with a binder such as carboxymethylcellulose, analiginate, gelatin, or polyvinyl pyrrolidone, a solution retardant suchas paraffin, a resorption accelerator such as a quaternary salt and/oran absorption agent such as bentonite, kaolin or dicalcium phosphate.The powder mixture can be granulated by wetting with a binder such assyrup, starch paste, acadia mucilage or solutions of cellulosic orpolymeric materials and forcing through a screen. As an alternative togranulating, the powder mixture can be run through the tablet machineand the result is imperfectly formed slugs broken into granules. Thegranules can be lubricated to prevent sticking to the tablet formingdies by means of the addition of stearic acid, a stearate salt, talc ormineral oil. The lubricated mixture is then compressed into tablets. Thecompounds of the present invention can also be combined with freeflowing inert carrier and compressed into tablets directly without goingthrough the granulating or slugging steps. A clear or opaque protectivecoating consisting of a sealing coat of shellac, a coating of sugar orpolymeric material and a polish coating of wax can be provided.Dyestuffs can be added to these coatings to distinguish different unitdosages.

[0270] Oral fluids such as solution, syrups and elixirs can be preparedin dosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared by dissolving thecompound in a suitably flavored aqueous solution, while elixirs areprepared through the use of a non-toxic alcoholic vehicle. Suspensionscan be formulated by dispersing the compound in a non-toxic vehicle.Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols andpolyoxy ethylene sorbitol ethers, preservatives, flavor additives suchas peppermint oil or saccharin, and the like can also be added.

[0271] Where appropriate, dosage unit formulations for oraladministration can be microencapsulated. The formulation can also beprepared to prolong or sustain the release as for example by coating orembedding particulate material in polymers, wax or the like.

[0272] The compounds of the present invention can also be administeredin the form of liposome delivery systems, such as small unilamellarvesicles, large unilamellar vesicles and multilamellar vesicles.Liposomes can be formed from a variety of phospholipids, such ascholesterol, stearylamine or phosphatidylcholines.

[0273] The compounds of the present invention can also be administeredin the form of liposome emulsion delivery systems, such as smallunilamellar vesicles, large unilamellar vesicles and multilamellarvesicles. Liposomes can be formed from a variety of phospholipids, suchas cholesterol, stearylamine or phosphatidylcholines.

[0274] Compounds of the present invention may also be delivered by theuse of monoclonal antibodies as individual carriers to which thecompound molecules are coupled. The compounds of the present inventionmay also be coupled with soluble polymers as targetable drug carriers.Such polymers can include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidephenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

[0275] The present invention includes pharmaceutical compositionscontaining 0.1 to 99.5%, more particularly, 0.5 to 90% of a compound ofthe formula (I) in combination with a pharmaceutically acceptablecarrier.

[0276] Likewise, the composition may also be administered in nasal,ophthalmic, otic, rectal, topical, intravenous (both bolus andinfusion), intraperitoneal, intraarticular, subcutaneous orintramuscular, inhalation or insufflation form, all using forms wellknown to those of ordinary skill in the pharmaceutical arts.

[0277] For transdermal administration, the pharmaceutical compositionmay be given in the form of a transdermal patch, such as a transdermaliontophoretic patch.

[0278] For parenteral administration, the pharmaceutical composition maybe given as an injection or a continuous infusion (e.g. intravenously,intravascularly or subcutaneously). The compositions may take such formsas suspensions, solutions or emulsions in oily or aqueous vehicles andmay contain formulatory agents such as suspending, stabilizing and/ordispersing agents. For administration by injection these may take theform of a unit dose presentation or as a multidose presentationpreferably with an added preservative. Alternatively for parenteraladministration the active ingredient may be in powder form forreconstitution with a suitable vehicle.

[0279] The compounds of the invention may also be formulated as a depotpreparation. Such long acting formulations may be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Thus, for example, the compounds of theinvention may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly-soluble salt.

[0280] Alternatively the composition may be formulated for topicalapplication, for example in the form of ointments, creams, lotions, eyeointments, eye drops, ear drops, mouthwash, impregnated dressings andsutures and aerosols, and may contain appropriate conventionaladditives, including, for example, preservatives, solvents to assistdrug penetration, and emollients in ointments and creams. Such topicalformulations may also contain compatible conventional carriers, forexample cream or ointment bases, and ethanol or oleyl alcohol forlotions. Such carriers may constitute from about 1% to about 98% byweight of the formulation; more usually they will constitute up to about80% by weight of the formulation.

[0281] For administration by inhalation the compounds according to theinvention are conveniently delivered in the form of an aerosol spraypresentation from pressurized packs or a nebulizer, with the use of asuitable propellant, e.g. dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, tetrafluoroethane,heptafluoropropane, carbon dioxide or other suitable gas. In the case ofa pressurized aerosol the dosage unit may be determined by providing avalve to deliver a metered amount. Capsules and cartridges of e.g.gelatin for use in an inhaler or insufflator may be formulatedcontaining a powder mix of a compound of the invention and a suitablepowder base such as lactose or starch.

[0282] The pharmaceutical compositions generally are administered in anamount effective for treatment or prophylaxis of a specific condition orconditions. Initial dosing in human is accompanied by clinicalmonitoring of symptoms, such symptoms for the selected condition. Ingeneral, the compositions are administered in an amount of active agentof at least about 100 μg/kg body weight. In most cases they will beadministered in one or more doses in an amount not in excess of about 20mg/kg body weight per day. Preferably, in most cases, dose is from about100 μg/kg to about 5 mg/kg body weight, daily. For administrationparticularly to mammals, and particularly humans, it is expected thatthe daily dosage level of the active agent will be from 0.1 mg/kg to 10mg/kg and typically around 1 mg/kg. It will be appreciated that optimumdosage will be determined by standard methods for each treatmentmodality and indication, taking into account the indication, itsseverity, route of administration, complicating conditions and the like.The physician in any event will determine the actual dosage which willbe most suitable for an individual and will vary with the age, weightand response of the particular individual. The effectiveness of aselected actual dose can readily be determined, for example, bymeasuring clinical symptoms or standard anti-inflammatory indicia afteradministration of the selected dose. The above dosages are exemplary ofthe average case. There can, of course, be individual instances wherehigher or lower dosage ranges are merited, and such are within the scopeof this invention. For conditions or disease states as are treated bythe present invention, maintaining consistent daily levels in a subjectover an extended period of time, e.g., in a maintenance regime, can beparticularly beneficial.

[0283] The compounds of the present invention are generally inhibitorsof the serine/threonine kinase p38 and are therefore also inhibitors ofcytokine production which is mediated by p38 kinase. Within the meaningof the term “inhibitors of the serine/threonine kinase p38” are includedthose compounds that interfere with the ability of p38 to transfer aphosphate group from ATP to a protein substrate according to the assaydescribed below.

[0284] Certain compounds of the present invention are also generallyinhibitors of JNK kinase and are therefore also inhibitors of cytokineproduction which is mediated by JNK kinase.

[0285] It is known that p38 and/or JNK kinase activity can be elevated(locally or throughout the body), p38 and/or JNK kinase can beincorrectly temporally active or expressed, p38 and/or JNK kinase can beexpressed or active in an inappropriate location, p38 and/or JNK kinasecan be constitutively expressed, or p38 and/or JNK kinase expression canbe erratic; similarly, cytokine production mediated by p38 and/or JNKkinase activity can be occurring at inappropriate times, inappropriatelocations, or it can occur at detrimentally high levels.

[0286] Accordingly, the present invention provides a method for thetreatment of a condition or disease state mediated by p38 and/or JNKkinase activity in a subject which comprises administering to saidsubject a therapeutically effective amount of a compound of formula (I)or a pharmaceutically acceptable salt or solvate thereof or aphysiologically functional derivative thereof. The compound may beadministered as a single or polymorphic crystalline form or forms, anamorphous form, a single enantiomer, a racemic mixture, a singlestereoisomer, a mixture of stereoisomers, a single diastereoisomer or amixture of diastereoisomers.

[0287] The present invention also provides a method of inhibitingcytokine production which is mediated by p38 and/or JNK kinase activityin a subject, e.g. a human, which comprises administering to saidsubject in need of cytokine production inhibition a therapeutic, orcytokine-inhibiting, amount of a compound of the present invention. Thecompound may be administered as a single or polymorphic crystalline formor forms, an amorphous form, a single enantiomer, a racemic mixture, asingle stereoisomer, a mixture of stereoisomers, a singlediastereoisomer or a mixture of diastereoisomers.

[0288] The present invention treats these conditions by providing atherapeutically effective amount of a compound of this invention. By“therapeutically effective amount” is meant a symptom-alleviating orsymptom-reducing amount, a cytokine-reducing amount, acytokine-inhibiting amount, a kinase-regulating amount and/or akinase-inhibiting amount of a compound. Such amounts can be readilydetermined by standard methods, such as by measuring cytokine levels orobserving alleviation of clinical symptoms. For example, the cliniciancan monitor accepted measurement scores for anti-inflammatorytreatments.

[0289] The compounds of the present invention can be administered to anysubject in need of inhibition or regulation of p38 and/or JNK kinase orin need of inhibition or regulation of p38 and/or JNK mediated cytokineproduction. In particular, the compounds may be administered to mammals.Such mammals can include, for example, horses, cows, sheep, pigs, mice,dogs, cats, primates such as chimpanzees, gorillas, rhesus monkeys, and,most preferably, humans.

[0290] Thus, the present invention provides methods of treating orreducing symptoms in a human or animal subject suffering from, forexample, rheumatoid arthritis, osteoarthritis, asthma, psoriasis,eczema, allergic rhinitis, allergic conjunctivitis, adult respiratorydistress syndrome, chronic pulmonary inflammation, chronic obstructivepulmonary disease, chronic heart failure, silicosis, endotoxemia, toxicshock syndrome, inflammatory bowel disease, tuberculosis,atherosclerosis, neurodegenerative disease, Alzheimer's disease,Parkinson's disease, epilepsy, multiple sclerosis, aneurism, stroke,irritable bowel syndrome, muscle degeneration, bone resorption diseases,osteoporosis, diabetes, reperfusion injury, graft vs. host reaction,allograft rejections, sepsis, systemic cachexia, cachexia secondary toinfection or malignancy, cachexia secondary to aquired immune deficiencysyndrome (AIDS), malaria, leprosy, infectious arthritis, leishmaniasis,Lyme disease, glomerulonephritis, gout, psoriatic arthritis, Reiter'ssyndrome, traumatic arthritis, rubella arthritis, Crohn's disease,ulcerative colitis, acute synovitis, gouty arthritis, spondylitis, andnon articular inflammatory conditions, for example,herniated/ruptured/prolapsed intervertebral disk syndrome, bursitis,tendonitis, tenosynovitis, fibromyalgic syndrome and other inflammatoryconditions associated with ligamentous sprain and regionalmusculoskeletal strain, pain, for example that associated withinflammation and/or trauma, osteopetrosis, restenosis, thrombosis,angiogenesis, cancer including breast cancer, colon cancer, lung canceror prostatic cancer, which comprises administering to said subject atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt or solvate thereof or a physiologicallyfunctional derivative thereof. A further aspect of the inventionprovides a method of treatment of a human or animal subject sufferingfrom rheumatoid arthritis, asthma, psoriasis, chronic pulmonaryinflammation, chronic obstructive pulmonary disease, chronic heartfailure, systemic cachexia, glomerulonephritis, Crohn's disease,neurodegenerative disease, Alzheimer's disease, Parkinson's disease,epilepsy and cancer including breast cancer, colon cancer, lung cancerand prostatic cancer, which comprises administering to said subject atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt or solvate thereof or a physiologicallyfunctional derivative thereof.

[0291] A further aspect of the invention provides a method of treatmentof a human or animal subject suffering from rheumatoid arthritis,asthma, psoriasis, chronic pulmonary inflammation, chronic obstructivepulmonary disease, chronic heart failure, systemic cachexia,glomerulonephritis, Crohn's disease and cancer including breast cancer,colon cancer, lung cancer and prostatic cancer, which comprisesadministering to said subject a therapeutically effective amount of acompound of formula (I) or a pharmaceutically acceptable salt or solvatethereof or a physiologically functional derivative thereof.

[0292] A further aspect of the invention provides a method of treatmentof a human or animal subject suffering from rheumatoid arthritis,neurodegenerative disease, Alzheimer's disease, Parkinson's disease andepilepsy which comprises administering to said subject a therapeuticallyeffective amount of a compound of formula (I) or a pharmaceuticallyacceptable salt or solvate thereof or a physiologically functionalderivative thereof.

[0293] A further aspect of the invention provides a compound of formula(I), or a pharmaceutically acceptable salt or solvate thereof or aphysiologically functional derivative thereof, for use in therapy.

[0294] A further aspect of the invention provides the use of a compoundof formula (I), or a pharmaceutically acceptable salt or solvate thereofor a physiologically functional derivative thereof, for the preparationof a medicament for the treatment of a condition or disease statemediated by p38 and/or JNK kinase activity or mediated by cytokinesproduced by p38 and/or JNK kinase activity.

[0295] A further aspect of the invention provides the use of a compoundof formula (I), or a pharmaceutically acceptable salt or solvate thereofor a physiologically functional derivative thereof, for the preparationof a medicament for the treatment of a condition or disease stateselected from rheumatoid arthritis, osteoarthritis, asthma, psoriasis,eczema, allergic rhinitis, allergic conjunctivitis, adult respiratorydistress syndrome, chronic pulmonary inflammation, chronic obstructivepulmonary disease, chronic heart failure, silicosis, endotoxemia, toxicshock syndrome, inflammatory bowel disease, tuberculosis,atherosclerosis, neurodegenerative disease, Alzheimer's disease,Parkinson's disease, epilepsy, multiple sclerosis, aneurism, stroke,irritable bowel syndrome, muscle degeneration, bone resorption diseases,osteoporosis, diabetes, reperfusion injury, graft vs. host reaction,allograft rejections, sepsis, systemic cachexia, cachexia secondary toinfection or malignancy, cachexia secondary to aquired immune deficiencysyndrome (AIDS), malaria, leprosy, infectious arthritis, leishmaniasis,Lyme disease, glomerulonephritis, gout, psoriatic arthritis, Reiter'ssyndrome, traumatic arthritis, rubella arthritis, Crohn's disease,ulcerative colitis, acute synovitis, gouty arthritis, spondylitis, andnon articular inflammatory conditions, for example,herniated/ruptured/prolapsed intervertebral disk syndrome, bursitis,tendonitis, tenosynovitis, fibromyalgic syndrome and other inflammatoryconditions associated with ligamentous sprain and regionalmusculoskeletal strain, pain, for example that associated withinflammation and/or trauma, osteopetrosis, restenosis, thrombosis,angiogenesis, and cancer including breast cancer, colon cancer, lungcancer or prostatic cancer.

[0296] A further aspect of the invention provides the use of a compoundof formula (I), or a pharmaceutically acceptable salt or solvate thereofor a physiologically functional derivative thereof, for the preparationof a medicament for the treatment of a condition or disease stateselected from rheumatoid arthritis, asthma, psoriasis, chronic pulmonaryinflammation, chronic obstructive pulmonary disease, chronic heartfailure, systemic cachexia, glomerulonephritis, Crohn's disease,neurodegenerative disease, Alzheimer's disease, Parkinson's disease,epilepsy, and cancer including breast cancer, colon cancer, lung cancerand prostatic cancer.

[0297] A further aspect of the invention provides the use of a compoundof formula (I), or a pharmaceutically acceptable salt or solvate thereofor a physiologically functional derivative thereof, for the preparationof a medicament for the treatment of a condition or disease stateselected from rheumatoid arthritis, asthma, psoriasis, chronic pulmonaryinflammation, chronic obstructive pulmonary disease, chronic heartfailure, systemic cachexia, glomerulonephritis, Crohn's disease andcancer including breast cancer, colon cancer, lung cancer and prostaticcancer. A further aspect of the invention provides the use of a compoundof formula (I), or a pharmaceutically acceptable salt or solvate thereofor a physiologically functional derivative thereof, for the preparationof a medicament for the treatment of a condition or disease stateselected from rheumatoid arthritis, neurodegenerative disease,Alzheimer's disease, Parkinson's disease and epilepsy.

[0298] The compounds of formula (I) and their salts, solvates andphysiologically functional derivatives may be employed alone or incombination with other therapeutic agents for the treatment of theabove-mentioned conditions. In particular, in rheumatoid arthritistherapy, combination with other chemotherapeutic or antibody agents isenvisaged. Combination therapies according to the present invention thuscomprise the administration of at least one compound of formula (I) or apharmaceutically acceptable salt or solvate thereof or a physiologicallyfunctional derivative thereof and at least one other pharmaceuticallyactive agent. The compound(s) of formula (I) or pharmaceuticallyacceptable salt(s) or solvate(s) thereof or physiologically functionalderivative(s) thereof and the other pharmaceutically active agent(s) maybe administered together or separately and, when administeredseparately, this may occur separately or sequentially in any order. Theamounts of the compound(s) of formula (I) or pharmaceutically acceptablesalt(s) or solvate(s) thereof or physiologically functionalderivative(s) thereof and the other pharmaceutically active agent(s) andthe relative timings of administration will be selected in order toachieve the desired combined therapeutic effect. Examples of otherpharmaceutically active agents which may be employed in combination withcompounds of formula (I) and their salts, solvates and physiologicallyfunctional derivatives for rheumatoid arthritis therapy include:immunosuppresants such as amtolmetin guacil, mizoribine and rimexolone;anti-TNFα agents such as etanercept, infliximab, diacerein; tyrosinekinase inhibitors such as leflunomide; kallikrein antagonists such assubreum; interleukin 11 agonists such as oprelvekin; interferon beta 1agonists; hyaluronic acid agonists such as NRD-101 (Aventis);interleukin 1 receptor antagonists such as anakinra; CD8 antagonistssuch as amiprilose hydrochloride; beta amyloid precursor proteinantagonists such as reumacon; matrix metalloprotease inhibitors such ascipemastat and other disease modifying anti-rheumatic drugs (DMARDs)such as methotrexate, sulphasalazine, cyclosporin A, hydroxychoroquine,auranofin, aurothioglucose, gold sodium thiomalate and penicillamine.

EXAMPLES

[0299] The following examples are illustrative embodiments of theinvention, not limiting the scope of the invention in any way. Reagentsare commercially available or are prepared according to procedures inthe literature. Example numbers refer to those compounds listed in thetables above. ¹H NMR spectra were obtained on VARIAN Unity Plus orBruker DPX NMR spectrophotometers at 300 or 400 MHz. Mass spectra wereobtained on Micromass Platform II mass spectrometers from Micromass Ltd.Altrincham, UK, using either Atmospheric Chemical Ionization (APCI) orElectrospray Ionization (ESI). Analytical thin layer chromatography(TLC) was used to verify the purity of some intermediates which couldnot be isolated or which were too unstable for full characterization,and to follow the progress of reactions. Unless otherwise stated, thiswas done using silica gel (Merck Silica Gel 60 F254). Unless otherwisestated, column chromatography for the purification of some compounds,used Merck Silica gel 60 (230-400 mesh), and the stated solvent systemunder pressure.

Example 1 2-(4-Fluorophenyl)-3-(4-pyridyl)-pyrazolo[1,5-a]pyridine

[0300]

[0301] a) 1-(4-Fluorophenyl)-2-trimethylsilylacetylene

[0302] 4-Fluoroiodobenzene (112 mL, 0.97 mol) and triethylamine (176 mL,1.26 mol) are dissolved in dry THF (1.2L) and nitrogen gas was bubbledthrough the solution for about 20 min. Copper (I) iodide (1.08 g-, 5.7mmol) and bis(triphenyphosphine)palladium dichloride (2.15 g, 3 mmol)are added and then trimethylsilylacetylene (178 mL, 1.3 mol) was addeddropwise over about 40 min with the temperature being maintained atabout 23° C. A large amount of precipitate forms (presumably Et₃NHCl)which necessitates mechanical stirring. Following complete addition ofthe trimethylsilylacetylene the mixture was allowed to stir at roomtemperature for about 18 h. The mixture was filtered and the solidwashed with cyclohexane. The combined filtrates are concentrated underreduce pressure to give a brown oil. Application of this oil to a pad ofsilica gel followed by elution with cyclohexane gave a yellow solution.Removal of the solvent gave the title compound as a yellow oil; 182.8 g(95%).

[0303] b) Methyl 3-(4-fluorophenyl)propiolate

[0304] A solution of 1-(4-fluorophenyl)-2-trimethylsilylacetylene (64 g,0.33 mol) in dry diethyl ether (400 mL) was cooled to 0° C. under anitrogen atmosphere. To this solution was added, dropwise over 45 min, asolution of tetrabutylammonium fluoride (1M in THF, 330 mL, 0.33 mol)via a dropping funnel maintaining the internal temperature below 2° C.The mixture was allowed to warm to room temperature over about 1 h.Diethyl ether (300 mL) was added to the mixture and the organic solutionwas washed with water, saturated brine and then dried (MgSO₄). Themagnesium sulfate was removed by filtration and the filtrate was cooledto about −78° C. n-Butyl lithium (1.6M in hexanes, 450 mL, 0.72 mol) wasadded dropwise via a dropping funnel over about 1 h while thetemperature was maintained below −66° C. After complete addition themixture was stirred at 78° C. for about 1 h and then a precooledsolution of methyl chloroformate (110 mL, 1.4 mol) in dry diethyl ether(200 mL) was added in a continuous stream as fast as possible. Themixture was allowed to cool to −78° C. and then allowed to warm to roomtemperature over 1.5 h. The organic reaction mixture was washed withwater and saturated brine and then dried (MgSO₄). The solvents areremove under reduced pressure and the residue dried under reducedpressure to give the title compound as a brown solid, 36.5 g (61%). ¹HNMR (CDCl₃) δ 7.58 (dd, 2H, J=9, 5.4 Hz), 7.07 (t, 2H, J=8.5 Hz), 3.84(s, 3H). MS (+ve ion electrospray) 178 (30), (M⁺).

[0305] c) Methyl2-(4-fluorophenyl)-pyrazolo[1,5-a]pyridine-3-carboxylate

[0306] A stirred solution of methyl 3-(4-fluorophenyl)propiolate (8.02g, 45 mmol) and 1-aminopyridinium iodide (10 g, 45 mmol) in dryacetonitrile (150 mL) was cooled to about 0° C. A solution of1,8-diazabicycloundec-7-ene (13.7 g, 90 mmol) in dry acetonitrile (50mL) was added dropwise over 1 h. The mixture was allowed to stir at roomtemperature for about 18 h. The reaction mixture was cooled in an icebath for about 30 min and the precipitate was collected by filtrationand washed with cold acetonitrile (10 mL). The solid was dried underreduced pressure to give the title compound as a white solid, 8.48 g(70%). ¹H NMR (CDCl₃) δ 8.50 (d, 1H, J=8.4 Hz), 8.18 (d, 1H, J=8.8 Hz),7.78 (m, 2H), 7.42 (t, 1H, J=8.4 Hz), 7.13 (t, 2H, J=8.8 Hz), 6.97 (td,1H, J=6.8, 1 Hz). MS (+ve ion electrospray) 271 (100), (MH⁺).

[0307] d) 2-(4-Fluorophenyl)-pyrazolo[1,5-a]pyridine-3-carboxylic Acid

[0308] A solution of methyl2-(4-fluorophenyl)-pyrazolo[1,5-a]pyridine-3-carboxylate (5.0 g, 18.5mmol) in 2N aqueous sodium hydroxide (50 ml) and methanol (30 mL) washeated at reflux for about 3 h. The mixture was filtered and thefiltrate was washed with diethyl ether (20 mL) and then concentratedunder reduced pressure to about half the original volume. Concentratedhydrochloric acid was added to adjust the pH to about 2 and theresulting solid was collected by filtration and washed with water anddried under vacuum to give the title compound as a white solid, 4.8 g(ca. 100%). ¹H NMR (d₆-DMSO) δ 12.43 (brs, 1H), 8.84 (d, 1H, J=6.9 Hz),8.14 (d, 1H, J=9 Hz), 7.82 (m, 2H), 7.57 (t, 1H, J=8.1 Hz), 7.28 (t, 2H,J=9 Hz), 7.15 (td, 1H, J=6.9, 1.2 Hz). MS (+ve ion electrospray) 257(100), (MH⁺).

[0309] e) 2-(4-Fluorophenyl)-3-bromopyrazolo[1,5-a]pyridine

[0310] To a solution of2-(4-fluorophenyl)-pyrazolo[1,5-a]pyridine-3-carboxylic acid (0.96 g,3.75 mmol) in dry DMF (10 mL) was added sodium bicarbonate (0.95 g, 11.3mmol) followed by N-bromosuccinimide (0.667 g, 3.75 mmol) and themixture was stirred at room temperature under a nitrogen atmosphere forabout 90 min. The mixture was poured into water (300 mL) and theresulting solid was collected by filtration and washed with water. Thesolid was dissolved in 10:1 chloroform:methanol (10 mL) and filteredthrough a pad (0.5 cm) of silica gel using 10:1 chloroform:methanol aseluent. The filtrate was evaporated to leave the title compound as a tansolid, 0.87 g (80%). ¹H NMR (d₆-DMSO) δ 8.7 (d, 1H, J=6.9 Hz), 8.02 (dd,2H, J=8.7, 5.7 Hz), 7.61 (d, 1H, J=8.4 Hz), 7.40 (t, 1H, J=6 Hz), 7.38(t, 2H, J=9 Hz), 7.04 (t, 1H, J=6.9 Hz). MS (+ve ion electrospray) 293(100), (MH⁺).

[0311] f) 2-(4-Fluorophenyl)-3-(4-pyridyl)-pyrazolo[1,5-a]pyridine

[0312] To a solution of2-(4-fluorophenyl)-3-bromopyrazolo[1,5-a]pyridine (0.2 g, 0.68 mmol) and4-(tributylstannyl)pyridine (0.38 g, 1 mmol) in dry toluene (10 mL) wasadded tetrakis(triphenylphosphine)palladium (0) (0.03 g, 0.03 mmol) andthe mixture was heated at reflux temperature under a nitrogen atmospherefor about 48 h. The mixture was cooled to room temperature and dilutedwith diethyl ether (40 mL). The mixture was poured into a 10% aqueoussolution of potassium fluoride (20 mL) and the mixture was stirred for 1h. The biphasic mixture was filtered through a pad (1 cm) ofdiatomaceous earth and the organic phase was separated. The aqueousphase was extracted with diethyl ether (10 mL) and the combined organicphases are washed with brine, dried (MgSO₄), filtered and the solventevaporated under reduced pressure. The residue was purified using silicagel chromatography with 20% EtOAc in hexanes, followed by 50% EtOAc inhexanes, as eluent to give the title compound as an off white solid,0.16 g (80%). ¹H NMR (CDCl₃) δ 8.58 (brs, 2H), 8.50 (d, 1H, J=7.2 Hz),7.63 (d, 1H, 9 Hz), 7.52 (m, 2H), 7.27-7.20 (m, 3H), 7.06 (t, 2H, J=8.7Hz), 6.86 dt, 1H, J=7, 1 Hz). MS (+ve ion electrospray) 290 (100),(MH⁺).

Example 22-(4-Fluorophenyl)-6-methyl-3-(4-pyridinyl)pyrazolo[1,5-a]pyridine

[0313]

[0314] a) 1-amino-3-methylpyridinium 2,4,6-trimethylbenzylsulfonate Tocold (0° C.) trifluoroacetic acid was addedN-tert-butoxycarbonyl-O-(mesitylsulfonyl)hydroxylamine in portions overabout 15 min. The solution was stirred for about 15 min at roomtemperature. The solution was poured into ice water and the resultingprecipitate was collected by filtration and air-dried for 5 min. Thesolid was dissolved in chloroform and this solution was dried (MgSO₄).The MgSO₄ was removed by filtration and the filtrate was added to asolution of 3-methylpyridine in chloroform. The mixture was stirred for45 min and then filtered To the filtrate was added diethyl ether and theproduct allowed to predipitate. The solid was collected by filtration,washed with diethyl ether and dried to give the title compound.

[0315] b) Methyl2-(4-fluorophenyl)-6-methyl-pyrazolo[1,5-a]pyridine-3-carboxylate

[0316] To a stirred solution of methyl 3-(4-fluorophenyl)propiolate(Example 1 b) and 1-amino-3-methylpyridinium2,4,6-trimethylbenzenesulfonate in dry acetonitrile was added, dropwiseover 10 min, a solution of 1,8-diazabicycloundec-7-ene in dryacetonitrile. The mixture was allowed to stir at room temperature forabout 18 h. The solvent was evaporated under reduced pressure and theresidue was partitioned between water and ethyl acetate and the organicphase separated. The aqueous was extracted with ethyl acetate and thecombined organic extracts are dried (MgSO₄), and the solvent removedunder vacuum. The residue was purified by chromatography on silica gelusing 10:1 hexanes:ethyl acetate as eluent to give the title compoundand also methyl2-(4-fluorophenyl)-4-methyl-pyrazolo[1,5-a]pyridine-3-carboxylate.

[0317] c)2-(4-fluorophenyl)-6-methyl-pyrazolo[1,5-a]pyridine-3-carboxylic Acid

[0318] In a similar manner as described in Example 1d, from methyl2-(4-fluorophenyl)-6-methyl-pyrazolo[1,5-a]pyridine-3-carboxylate wasobtained2-(4-fluorophenyl)-6-methyl-pyrazolo[1,5-a]pyridine-3-carboxylic acid asa white solid. ¹H NMR (d₆-DMSO) δ 8.69 (s, 1H), 8.07 (d, 1H, J=9.1 Hz),7.84 (dd, 2H, J=14.0 Hz), 7.44 (d, 1H, J=9.1 Hz), 7.28 (t, 2H, J=17.7Hz), 2.51 (s, 3H). MS (+ve electrospray) 270 (100), (M+).

[0319] d) 2-(4-fluorophenyl)-3-bromo-6-methyl-pyrazolo[1,5-a]pyridine

[0320] Following the procedure given in Example 1e, from2-(4-fluorophenyl)-6-methyl-pyrazolo[1,5-a]pyridine-3-carboxylic acidwas obtained 2-(4-fluorophenyl)-3-bromo-6-methyl-pyrazolo[1,5-a]pyridineas a white solid. ¹H NMR (CDCl₃) δ 8.27 (s, 1H), 8.05 (m, 2H), 7.47 (d,1H, J=9.0 Hz), 7.21 (m, 2H), 7.12 (d, 1H, J=9.0 Hz), 2.40 (s, 3H). MS(+ve electrospray) 306 (60), (MH+).

[0321] e)2-(4-Fluorophenyl)-6-methyl-3-(4-pyridinyl)pyrazolo[1,5-a]pyridine

[0322] In a similar manner as described in Example if, from2-(4-fluorophenyl)-3-bromo-6-methyl-pyrazolo[1,5-a]pyridine (0.1 g, 0.33mmol), and 4-tri-n-butylstannylpyridine (0.17 g, 0.46 mmol) was obtainedthe title compound as a white solid 0.015 g (14%). This material wasdissolved in diethyl ether and treated with HCl in diethyl ether toafford the corresponding hydrochloride salt. ¹H NMR (d₆-DMSO) δ 8.78 (s,1H), 8.72 (d, 2H, J=6.5 Hz), 7.94 (d, 1H, J=9.2 Hz), 7.78 (d, 2H, J=6.6Hz), 7.60 (m, 2H), 7.48 (d, 1H, J=9.2 Hz), 7.33 (t, 2H, J=17.6 Hz), 2.40(s, 3H). MS (+ve electrospray) 304 (100), (MH+).

Example 32-(4-Fluorophenyl)-5-methyl-3-(4-pyridinyl)pyrazolo[1,5-a]-pyridine

[0323]

[0324] In a similar manner as described in Example 2a, 2b, 1d, 1e and1f, from 4-methylpyridine was obtained the title compound as a whitesolid. This material was dissolved in diethyl ether and treated with HClin diethyl ether to afford the corresponding hydrochloride salt. ¹H NMR(CDCl₃) δ 8.50 (d, 2H, J=6.2 Hz), 8.44 (d, 1H, J=6.9 Hz), 7.67 (d, 2H,J=6.2 Hz), 7.57 (s, 1H), 7.44 (m, 2H), 7.12 (t, 2H, J=17.0 Hz), 6.87 (d,1H, J=7.1 Hz), 2.49 (s, 3H). MS (+ve electrospray) 340 (10), (MH⁺).

Example 42-(4-Fluorophenyl)-4-methyl-3-(4-pyridinyl)pyrazolo[1,5-a]-pyridine

[0325]

[0326] In a similar manner as described in Example 1d, 1e and if frommethyl 2-(4-fluorophenyl)-4-methyl-pyrazolo[1,5-a]pyridine-3-carboxylate(prepared as a side-product in Example 2b) was obtained the titlecompound as a white solid. This material was dissolved in diethyl etherand treated with HCl in diethyl ether to afford the correspondinghydrochloride salt. ¹H NMR (d₆-DMSO) δ 8.78 (d, 2H, J=6.0 Hz), 7.70 (d,1H, J=6.8 Hz), 7.85 (d, 2H, J=6.0 Hz), 7.37 (m, 2H), 7.18 (m, 3H), 7.00(t, 1H, J=13.9 Hz), 2.12 (s, 3H). MS (+ve electrospray) 340 (100),(MH⁺).

Example 52-(4-Fluorophenyl)-5-methoxy-3-(4-pyridinyl)pyrazolo[1,5-a]pyridine

[0327]

[0328] In a similar manner as described in Examples 2a, 2b, 1d, 1e and1f, from 4-methoxypyridine was obtained the title compound. ¹H NMR(d₆-DMSO) δ 3.84 (s, 3H), 6.69 (dd, 1H, J=2.8, 7.6 Hz), 6.95 (d, 1H,J=2.4 Hz), 7.24 (m, 4H), 7.47 (dd, 2H, J=6.0, 8.8 Hz), 8.51 (d, 2H,J=6.0 Hz), 8.63 (d, 1H, J=6.0 Hz).

Example 62-(4-Fluorophenyl)-5-hydroxymethyl-3-(4-pyridinyl)pyrazolo[1,5-a]pyridine

[0329]

[0330] a) 4-(tert-butyidimethylsilyloxymethyl)pyridine

[0331] To a stirred solution of tert-butyldimethylsilyl chloride (16.6g, 0.11 mol) and imidazole (16.3 g, 0.24 mol) in DMF (20 mL) was added4-pyridinemethanol (10 g, 0.09 mol) and the mixture was stirred forabout 1 h. The reaction mixture was poured into diethyl ether (200 mL)and the resulting solution was washed with water (100 mL). The aqueousphase was extracted with diethyl ether and the combined organic phasesare washed with water, brine and dried (MgSO₄). The solvent wasevaporated under reduced pressure to leave4-(tertbutyidimethylsilyloxymethyl)pyridine, 22.5 g. ¹H NMR (d₆-DMSO) d8.49 (d, 2H), 7.27 (d, 2H), 4.62 (s, 2H), 0.9 (s, 9H), 0.09 (s, 6H).

[0332] b)2-(4-Fluorophenyl)-5-hydroxymethyl-3-(4-pyridinyl)-pyrazolo[1,5-a]pyridine

[0333] Then, in a similar manner as described in Examples 2a, 2b, 1d, 1eand 1f, from 4-(tert-butyldimethylsilyloxymethyl)pyridine was obtainedthe title compound, ¹H NMR (d₆-DMSO) δ 4.55 (d, 2H, J=5.6 Hz), 5.45 (t,1H, J=5.6 Hz), 6.94 (d, 1H, J=6.8 Hz), 7.23 (t, 2H, J=8.8 Hz), 7.27 (d,2H, J=6.0 Hz), 7.51 (dd, 2H, J=5.6, 8.4 Hz), 8.60 (s, 1H), 8.55 (d, 2H,J=5.6 Hz), 8.71 (d, 1H, J=7.2 Hz). MS (AP+) m/z 320 (M⁺+H).

Example 72-(4-Fluorophenyl)-4-hydroxymethyl-3-(4-pyridinyl)-pyrazolo[1,5-a]pyridine

[0334]

[0335] a) 3-(tert-butyldimethylsilyloxymethyl)pyridine

[0336] In a similar manner as described in Example 6a,3-(tert-butyldimethylsilyloxymethyl)pyridine was obtained from3-pyridinemethanol, (10 g, 0.09 mol), 22 g. ¹H NMR (d₆-DMSO) δ 8.50 (s,1H), 8.44 (d, 1H), 7.68 (d, 1H), 7.34 (dd, 1 h), 4.71 (s, 1H), 0.87 (s,9H), 0.06 (s, 6H).

[0337] b)2-(4-Fluorophenyl)-4-hydroxymethyl-3-(4-pyridinyl)-pyrazolo[1,5-a]pyridine

[0338] In a similar manner as described in Examples 2a, 2b, 1d, 1e and1f, from 3-(tert-butyldimethylsilyloxymethyl)pyridine was obtained thetitle compound, ¹H NMR (d₆-DMSO) δ 4.18 (dd, 2H, J=5.2 Hz), 5.22 (t, 1H,J=5.2 Hz), 6.97 (t, 1H, J=6.8 Hz), 7.13 (t, 2H, J=8.8 Hz), 7.30 (d, 2H,J=7.2 Hz), 7.37 (m, 4H), 8.56 (d, 2H, J=5.6 Hz), 8.64 (d, 1H, J=7.2 Hz).

Example 86-Fluoro-2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridine

[0339]

[0340] In a similar manner as described in Examples 2a, 2b, 1d, 1e andif, from 3-fluoropyridine was obtained the title compound as a whitesolid which was converted to a hydrochloride salt. ¹H NMR (d₆-DMSO) δ9.24 (s, 1H), 8.71 (di 2H, J=5.3 Hz), 8.00 (m, 2H), 7.72 (d, 2H, J=5.3Hz), 7.70 (m, 1H), 7.55 (m, 2H), 7.28 (t, 2H, J=17.6 Hz). MS (+veelectrospray) 308 (40), (MH⁺).

Example 94-Fluoro-2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridine

[0341]

[0342] In a similar manner as described in Examples 2a, 2b, 1d, 1e and1f, from 3-fluoropyridine was obtained the title compound. ¹H NMR(d₆-DMSO) δ 7.05 (m, 1H), 7.27 (m, 3H), 7.36(m, 2H), 7.48 (m, 2H), 8.59(d, 2H, J=7.6 Hz), 8.74 (d, 1H, J=9.2 Hz). MS (ES+) m/z 308 (MH⁺).

Example 10[2-(4-Fluorophenyl)-3-(4-pyridyl)pyrazolo[1,5-a]pyridin-5-yl]methyl2-methylbenzoate

[0343]

[0344]2-(4-Fluorophenyl)-5-hydroxymethyl-3-(4-pyridinyl)pyrazolo[1,5-a]pyridine(Example 6. 50 mg, 0.157 mmol), triphenyl phosphine (82 mg, 0.314 mmol)and 2-methylbenzoic acid (0.314 mmol) are dissolved in dry THF (3 mL).To the stirred solution is added diethyl azodicarboxylate (55 mg, 0.314mmol) dropwise. The resulting solution is stirred at room temperatureuntil reaction is complete as determined by TLC and then diluted withhexane/ethyl acetate (30 mL of a 1:1 mixture) and washed with water(×3). The organic phase is then shaken with dilute hydrochloric acid. Incases were the hydrochloride salt of the product deposits at this stageit is filtered off, washed with water and then hexane and dried. If nodeposit is observed, the acidic phase is separated, washed once withhexane/ethyl acetate (15 mL of a 1:1 mixture) and basified withsaturated sodium bicarbonate solution. This is then extracted withdichloromethane (15 mL) five times and the dichloromethane solutiondried (MgSO₄), filtered and concentrated to give the title compound. ¹HNMR (d₆-DMSO) δ 2.50 (s, 3H), 5.41 (s, 2H), 7.25-7.33 (m, 5H), 7.48 (t,J=7.4 Hz, 1H), 7.56 (dd, J=5.6, 8.5 Hz, 2H), 7.73 (d, J=5.8 Hz, 2H),7.88 (d, J=7.9 Hz, 1H), 8.06 (s, 1H), 8.71 (d, J=6.2 Hz, 2H), 8.92 (d,J=7.1 Hz, 1H). APESI-MS m/z 438 (M+1)⁺.

Example 11[2-(4-Fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridin-5-yl]methylIsonicotinate

[0345]

[0346]2-(4-Fluorophenyl)-5-hydroxymethyl-3-(4-pyridinyl)pyrazolo[1,5-a]pyridine(Example 6. 30 mg, 0.094 mmol) and 4-pyridinecarboxylic acid (0.12 mmol)are dissolved in dimethylformamide (0.5 mL) and diethyl cyanophosphonate(35 mg, 0.2 mmol, 93% grade), followed by triethylamine (35 mg, 0.35mmol) are added dropwise. The resulting solution is stirred at roomtemperature until the reaction is complete as determined by TLC and thendiluted with hexane/ethyl acetate (30 mL of a 1:1 mixture) and washedwith water (3×). The organic phase is then shaken with dilutehydrochloric acid. In cases were the hydrochloride salt of the productdeposits at this stage it is filtered off, washed with water and thenhexane and dried. If no deposit is observed, the acidic phase isseparated, washed once with hexane/ethyl acetate (15 mL of a 1:1mixture) and basified with saturated sodium bicarbonate solution. Thisis then extracted with dichloromethane (15 mL) five times and thedichloromethane solution dried (MgSO₄), filtered and concentrated togive the title compound. ¹H NMR (d₆-DMSO) δ 5.43 (s, 2H), 7.15 (d, J=6.9Hz, 1H), 7.25 (t, J=8.8 Hz, 2H), 7.30 (d, J=5.9 Hz, 2H), 7.50-7.53 (m,2H), 7.84-7.87 (m, 3H), 8.55 (d, J=5.7 Hz, 2H), 8.79 (d, J=5.9 Hz, 2H),8.82 (d, J=7.1 Hz, 1H); APESI-MS m/z 425 (M+1)⁺.

Example 12[2-(4-Fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridin-5-yl]methylNicotinate

[0347]

[0348] In a similar manner as described for Example 11, using3-pyridinecarboxylic acid in place of 4-pyridinecarboxylic acid, isobtained the title compound. ¹H NMR (d₆-DMSO) δ 5.43 (s, 2H), 7.16 (d,J=7.1 Hz, 1H), 7.24 (t, J=8.8 Hz, 2H), 7.30 (d, J=5.7 Hz, 2H), 7.50-7.57(m, 3H), 7.86 (s, 1H), 8.31 (d, J=7.8 Hz, 1H), 8.54 (d, J=5.7 Hz, 2H),8.80-8.82 (m, 2H), 9.11 (s, 1H); APESI-MS m/z 425 (M+1)⁺.

Example 13[2-(4-Fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridin-5-yl]methyl3-bromo-2-thiophenecarboxylate

[0349]

[0350] In a similar manner as described for Example 11, using3-bromothiophene-2-carboxylic acid in place of 4-pyridinecarboxylicacid, is obtained the title compound. ¹H NMR (d₆-DMSO) δ 5.43 (s, 2H),7.21 (d, J=7.3 Hz, 1H), 7.26-7.31 (m, 3H), 7.56 (t, J=7.1 Hz, 2H),7.68-7.70 (m, 2H), 8.01 (d, J=5.2 Hz, 1H), 8.04 (s, 1H), 8.70 (d, J=5.9Hz, 2H), 8.90 (d, J=7.1 Hz, 2H), APESI-MS m/z 508/510 (M+1)⁺.

Example 14[2-(4-Fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridin-5-yl]methyl6-aminonicotinate

[0351]

[0352] In a similar manner as described for Example 11, using2-amino-5-pyridinecarboxylic acid in place of 4-pyridinecarboxylic acid,is obtained the title compound. ¹H NMR (d₆-DMSO) δ 5.31 (s, 2H), 6.43(d, J=8.8 Hz, 1H), 6.87 (bs, 2H), 7.08 (d, J=7.3 Hz, 1H), 7.26 (t, J=8.8Hz, 2H), 7.29 (d, J=5.8 Hz, 2H), 7.51 (dd, J=5.6, 8.2 Hz, 2H), 7.79 (s,1H), 7.82 (dd, J=2.2, 8.8 Hz, 1H), 8.54 (m, 3H), 8.79 (d, J=7.1 Hz, 1H).

Example 15[2-(4-Fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridin-5-yl]methyl5-(methylsulfonyl)-2-thiophenecarboxylate

[0353]

[0354] In a similar manner as described for Example 11, using2-methylsulfonyl-5-thiophenecarboxylic acid in place of4-pyridinecarboxylic acid, is obtained the title compound. ¹H NMR(d₆-DMSO) δ 3.47 (s, 3H), 5.48 (s, 2H), 7.16 (d, J=7.1 Hz, 1H), 7.30 (t,J=8.8 Hz, 2H), 7.36 (d, J=5.7 Hz, 2H), 7.58 (dd, J=5.7, 8.9 Hz, 2H),7.91 (d, J=3.6 Hz, 2H), 7.,92 (d, J=4.0 Hz, 1H), 8.61 (d, J=5.9 Hz, 2H),8.88 (d, J=7.1 Hz, 1H), APESI-MS m/z 508 (M+1)⁺.

Example 16[2-(4-Fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridin-5-yl]methyl2-aminonicotinate

[0355]

[0356] In a similar manner as described for Example 11, using2-amino-3-pyridinecarboxylic acid in place of 4-pyridinecarboxylic acid,is obtained the title compound. ¹H NMR (d₆-DMSO) δ 5.35 (s, 2H), 6.60(dd, J=4.6, 7.8 Hz, 1H), 7.10 (d, J=7.2 Hz, 1H), 7.16 (bs, 2H), 7.23 (t,J=8.8 Hz, 2H), 7.29 (d, J=6.0 Hz, 2H), 7.51 (dd, J=5.7, 8.6 Hz, 2H),7.82 (s, 1H), 8.08 (d, J=7.9 Hz, 1H), 8.20 (m, 1H), 8.54 (d, J=6.0 Hz,2H), 8.80 (d, J=7.1 Hz, 1H); APESI-MS m/z 440 (M+1)⁺.

Example 17[2-(4-Fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridin-5-yl]methyl3-(aminosulfonyl)-4-chlorobenzoate

[0357]

[0358] In a similar manner as described for Example 11, using3-aminosulfonyl-4-chlorobenzoic acid in place of 4-pyridinecarboxylicacid, is obtained the title compound. ¹H NMR (d₆-DMSO) δ 5.46 (s, 2H),7.11 (d, J=7.4 Hz, 1H), 7.24 (t, J=8.9 Hz, 2H), 7.30 (d, J=6.0 Hz, 2H),7.52 (dd, J=5.6, 8.5 Hz, 2H), 7.58 (s, 2H), 7.81 (d, J=8.4 Hz, 1H), 7.87(s, 1H), 7.95 (dd, J=2.1, 8.1 Hz, 1H), 8.25 (d, J=2 Hz, 1H), 8.55 (d,J=5.8 Hz, 2H), 8.83 (d, J=7.2 Hz, 1H); APESI-MS m/z 537/539 (M+1)⁺.

Example 18[2-(4-Fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridin-5-yl]methyl3-methyl-2-thiophenecarboxylate

[0359]

[0360] In a similar manner as described for Example 11, using3-methyl-2-thiophenecarboxylic acid in place of 4-pyridinecarboxylicacid, is obtained the title compound. ¹H NMR (d₆-DMSO) δ 2.47 (s, 3H),5.37 (s, 2H), 7.07 (d, J=4.9 Hz, 1H), 7.12 (d, J=7.1 Hz, 1H), 7.27 (t,J=8.9 Hz, 2H), 7.49 (d, J=5.1 Hz, 2H), 7.53 (dd, J=5.6, 8.6 Hz, 2H),7.80 (d, J=5 Hz, 1H), 7.91 (s, 1H), 8.63 (d, J=5.9 Hz, 2H), 8.87 (d,J=7.1 Hz, 1H), APESI-MS m/z 444 (M+1)⁺.

Example 19[2-(4-Fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridin-5-yl]methyl2-methoxybenzoate

[0361]

[0362] In a similar manner as described for Example 11, using2-methoxybenzoic acid in place of 4-pyridinecarboxylic acid, is obtainedthe title compound. ¹H NMR (d₆-DMSO) δ 3.75 (s, 3H), 5.39 (s, 2H), 7.01(t, J=7.4 Hz, 1H), 7.15 (d, J=8.6 Hz, 1H), 7.20 (d, J=7.0 Hz, 1H), 7.28(t, J=8.7 Hz, 2H), 7.50-7.60 (m, 3H), 7.62-7.73 (m, 3H), 7.98 (s, 1H),8.69 (d, J=6.1 Hz, 2H), 8.90 (d, J=6.9 Hz, 1H); APESI-MS m/z 454 (M+1)⁺.

Example 20[2-(4-Fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridin-5-yl]methyl2,3-dichlorobenzoate

[0363]

[0364] In a similar manner as described for Example 11, using2,3-dichlorobenzoic acid in place of 4-pyridinecarboxylic acid, isobtained the title compound. ¹H NMR (d₆-DMSO) δ 5.43 (s, 2H), 7.11 (d,J=7.2 Hz, 1H), 7.24 (t, J=8.8 Hz, 2H), 7.30 (d, J=5. Hz, 2H), 7.47-7.53(m, 3H), 7.78 (d, J=5.4 Hz, 1H), 7.83-7.87 (m, 2H), 8.55 (d, J=5.9 Hz,2H), 8.81 (d, J=7.1 Hz, 1H); APESI-MS m/z 492/494/496 (M+1)⁺.

Example 212-[2-(4-Fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridin-5-yl]methyl-1H-isoindole-1,3(2H)-dione

[0365]

[0366]2-(4-Fluorophenyl)-5-hydroxymethyl-3-(4-pyridinyl)pyrazolo[1,5-a]pyridine(Example 6. 68 mg, 0.213 mmol), triphenyl phosphine (168 mg, 0.64 mmol)and phthalimide (63 mg, 0.43 mmol) are dissolved in dry THF (3 mL). Thestirred solution is cooled to 0° C. and diethyl azodicarboxylate (105 mgof 85% grade, 0.51 mmol) is added dropwise. The solution is stirred at0° C. for 2 h during which time a white solid deposits and then stirredfor 16 h at room temperature. The solution is then diluted with ether(20 mL) and the deposited solid filtered off. The solid is washed withether and dried to give the first batch of product (20 mg). The ethersolution is then washed with water and then extracted with dilutehydrochloric acid. A portion of the product deposits and is filteredoff, washed twice with ether and dried to give the product as thehydrochloride salt (16 mg). The acidic phase is washed with ether andthen made alkaline with sodium bicarbonate solution. Extraction withethyl acetate (50 mL×3) followed by drying (MgSO₄) and concentrationgives the product as an off-white solid (32 mg). ¹H NMR (d₆-DMSO) δ 4.83(s, 2H), 6.91 (dd, J=1.8, 7.2 Hz, 1H), 7.22 (t, J=8.9 Hz, 2H), 7.26 (d,J=5.9 Hz, 2H), 7.49 (dd, J=5.6, 8.6 Hz, 2H), 7.71 (s, 1H), 7.81-7.89 (m,4H), 8.54 (d, J=4.7 Hz, 2H), 8.72 (d, J=7.1 Hz, 1H); APESI-MS m/z 449(M+1)⁺

Example 22[2-(4-Fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridin-5-yl]methanamine

[0367]

[0368][2-(4-Fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridin-5-yl]methyl3-(aminosulfonyl)-4-chlorobenzoate (Example 17 106 mg, 0.23 mmol) isdissolved in ethanol (10 mL) and hydrazine (64 mg, 2 mmol) added. Thesolution is refluxed for 6 h and allowed to cool. A precipitate ofphthalhydrazide is filtered off and the mother liquor concentrated todryness. The crude solid is taken up in dilute hydrochloric acid (20mL), and washed twice with ethyl acetate (15 mL) followed bybasification with sodium hydroxide solution. The solution is extractedfive times with dichloromethane (20 mL), dried (MgSO₄) and concentratedto give a solid (43 mg). Purified by preparative TLC, eluting with ethylacteate plus 2% methanol, to give the title compound, 23 mg. ¹H NMR(d₆-DMSO) δ 3.75 (s, 2H), 6.97 (d, J=7.3 Hz, 1H), 7.22 (t, J=8.9 Hz,2H), 7.28 (d, J=5.9 Hz, 2H), 7.50 (dd, J=5.7, 8.4 Hz, 2H), 7.64 (s, 1H),8.53 (d, J=5.7 Hz, 2H), 8.68 (d, J=7.2 Hz, 1H); APESI-MS m/z 319 (M+1)⁺.

Example 232-(4-Fluorophenyl)-3-(4-pyridinyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridine

[0369]

[0370] In a similar manner as described in Examples 2a, 2b, 1d, 1e and1f, from 3-trifluoromethylpyridine was obtained the title compound as awhite solid. ¹H NMR (d₆-DMSO) δ 7.27 (t, 2H, J=8.8 Hz), 7.32 (d, 2H,J=6.0 Hz), 7.54 (m, 3H), 7.87 (d, 2H, J=9.6 Hz), 8.58 (d, 2H, J=5.6 Hz),9.47 (s, 1H). MS (ES+) m/z 358 (M⁺+H).

Example 24 2-(4-Fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridin-5-ol

[0371]

[0372] A solution of2-(4-fluorophenyl)-3-(4-pyridyl)-5-methoxypyrazolo[1,5-a]pyridine(Example 5. 0.05 g, 0.16 mmol) in dry CH₂Cl₂ was cooled to about −78° C.under nitrogen. Boron tribromide (0.8 mL of a 1M solution in CH₂Cl₂, 0.8mmol) was added dropwise and the mixture was stirred and warmed to roomtemperature over about 24 h. Ice was added to the reaction mixture andthe resulting slurry was stirred for about 15 min. The CH₂Cl₂ wasevaporated under vacuum and the resulting aqueous slurry was treatedwith conc hydrochloric acid (1 mL) and stirred. The aqueous solution wasbasified by the addition of a saturated solution of NaHCO₃, and theresulting solid was collected by filtration and was dried under vacuumto give the title compound.

Example 255-(n-Butoxy)-2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridine

[0373]

[0374] 2-(4-Fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridin-5-ol(Example 24. 0.5 g, 1.63 mmol) was dissolved in dimethylformamide (10mL) and potassium tert butoxide (2.5 mL of a 1 M solution in THF, 2.5mmol) was added dropwise to the stirred solution. After 10 minutesiodobutane (2 mmol) was added and the reaction stirred at roomtemperature. Second additions of iodobutane (0.88 mmol) and 1M potassiumtertbutoxide (2.5 mL, 1 mmol) were made after 4 h and reaction stirredfurther until complete by TLC. Water (100 mL) was added and theresulting aqueous solution was extracted with with dichloromethane(4×100 mL), the combined organic solution was dried (MgSO₄), filteredand concentrated to give the crude product. This was purified either bysilica gel chromatography to give the title compound (58%). ¹H NMR(d₆-DMSO) δ 0.93 (t, J=7.3 Hz, 3H), 1.43 (quintet, J=7.3 Hz, 2H), 1.74(quintet, J=7.3 Hz, 2H), 4.13 (t, J=6.9 Hz, 2H), 6.84 (dd, J=2.4, 7.5Hz, 1H), 7.21 (d, J=2.4 Hz, 1H), 7.28 (t, J=8.8 Hz, 2H), 7.53 (dd,J=0.5, 8.8 Hz, 2H), 7.73 (d, J=6.4 Hz, 2H), 8.65 (d, J=6.4 Hz, 2H), 8.74(d, J 7.5 Hz, 1H); APESI-MS m/z 362 (M+1)⁺.

Example 265-(Benzyloxy)-2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridine

[0375]

[0376] In a similar manner as described in Example 25, using benzylbromide in place of iodobutane, was obtained the title compound (43%).¹H NMR (d₆-DMSO) δ 5.20 (s, 2H), 6.77 (dd, J=2.5, 7.5 Hz, 1H), 7.08 (d,J=2.5 Hz, 1H), 7.19-7.31 (m, 4H), 7.34 (d, J=7.1 Hz, 1H), 7.40 (t, J=7.4Hz, 2H), 7.45-7.49 (m, 4H), 8.51 (d, J=5.6 Hz, 2H), 8.66 (d, J=7.5 Hz,1H); APESI-MS m/z 396 (M+1)⁺

Example 272-(4-Fluorophenyl)-3-(2-fluoro-4-pyridinyl)pyrazolo[1,5-a]-pyridine

[0377]

[0378] A solution of 3-bromo-2-(4-fluorophenyl)-pyrazolo[1,5-a]pyridine(Example le. 1.30 g, 4.5 mmol), 2-fluoro-4-pyridinylboronic acid(Example 46a. 694 mg, 4.9 mmol) anddichlorobis(triphenylphosphine)palladium (316 mg, 0.45 mmol) in DMF (100mL) was placed in a pre-heated oil bath at 110° C. To the reaction wasadded, in a dropwise manner, 2M aqueous sodium carbonate (4.5 mL, 9.0mmol). The reaction was allowed to stir for 2 h and then cooled to roomtemperature and filtered through a pad of Celite. The Celite pad waswashed with ethyl acetate and the filtrate was concentrated to drynessat 50° C. under vacuum. The residue was partitioned between ethylacetate and water. The layers were separated and the organic phase wasdried (MgSO₄). The drying agent was removed by filtration and thefiltrate was concentrated and purified by silica gel chromatography toyield the title compound (378 mg, 1.23 mmol, 27%). ¹H NMR (CDCl₃) δ 8.57(d, 1H, J=6.9 Hz), 8.22(d, 1H, J=5.4 Hz), 7.7(d, 1H, J=9.0 Hz), 7.75(m,2H), 7.33(m, 1H), 7.14(m, 3H), 6.95(m, 2H). MS (ES+ve) 308 (100, M+).

Example 284-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-[2-(1H-imidazol-5-yl)ethyl]-2-pyridinamine

[0379]

[0380] In a sealed-tube was combined2-(4-fluorophenyl)-3-(2-fluoro-4-pyridinyl)pyrazolo[1,5-a]pyridine(Example 27. 30 mg, 0.10 mmol) and histamine (40 mg, 0.36 mmol), and thereaction was placed in a pre-heated oil bath at 140° C. The reaction wasstirred at 140° C. until consumption of starting material was indicatedby TLC analysis (50% ethyl acetate in hexanes). The contents of thesealed-tube were transferred to a flask and concentrated to dryness at50° C. under high vacuum. The residue was purified by silica gelchromatography to yield the title compound, 23 mg (0.06 mmol, 60%). ¹HNMR (d₆-DMSO) δ 11.8 (brs, 1H), 8.73 (d, 1H, J=6.8 Hz), 7.94 (d, 1H,J=5.3 Hz), 7.63 (d, 1H, J=9.3 Hz), 7.57 (dd, 2H, J=5.3, 8.6 Hz), 7.48(s, 1H), 7.30 (t, 1H, J=7.6 Hz), 7.23 (t, 2H, J=9.0 Hz), 6.97 (t, 1H,J=6.8 Hz), 6.75 (brs, 1H), 6.57 (br t, 1H, J=5.3 Hz), 6.44 (s, 1H), 6.33(d, 1H, J=5.3 Hz), 3.41 (q, 2H, J=6.6 Hz), 2.7 (t, 2H, J=6.6 Hz). MS(ES+ve): 399.1 (50, M+), 305.3 (90), 169.4 (100).

Example 29N-Butyl-4-[2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyridinamine

[0381]

[0382] In a similar manner as described in Example 28, using butylaminein place of histamine, was obtained the title compound. ¹H NMR (CD₂Cl₂)δ 8.49 (d, 1H, J=7.2 Hz), 8.01 (d, 1H. J=5.2 Hz), 7.62 (m, 3H), 7.21(m,1H,), 7.07(t, 2H, J=8.8 Hz), 6.85 (m, 2H), 6.54 (dd, 1H, J=4.8, 0.8 Hz),6.32 (s, 1H), 3.16 (quart, 2H, J=6.4 Hz), 1.53 (quint, 2H, J=7.2 Hz),1.37 (sext, 2H, J=Hz), 0.92 (t, 3H, J=7.2. Hz). MS (ES+ve) 361 (100,M⁺).

Example 303-(4-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyridinylamino)-1-propanol

[0383]

[0384] In a similar manner as described in Example 28, using3-hydroxypropylamine in place of histamine, was obtained the titlecompound. ¹H NMR (CD₂Cl₂) δ 8.55 (d, 1H, J=6.9 Hz), 8.04 (d, 1H, J=5.4Hz), 7.66 (m, 3H), 7.26 (m, 2H), 7.13 (t, 2H, J=8.7 Hz), 6.90 (t, 1H,J=6.9 Hz), 6.57 (d, 1H, J=5.1 Hz), 6.43 (s, 1H), 4.50 (t, 1H, J=5.7 Hz),3.66 (t, 2H, J=5.7 Hz), 3.55 (quart, 2H, J=6.0 Hz), 1.76 (quint, 2H,J=5.7 Hz). MS (ES+ve): 363 (100, M⁺).

Example 31N-(4-Chlorobenzyl)-4-[2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyridinamine

[0385]

[0386] In a similar manner as described in Example 28, using4-chlorobenzylamine in place of histamine, was obtained the titlecompound. ¹H NMR (CD₂Cl₂) δ 8.53 (d, 1H, J=6.9 Hz), 8.04 (d, 1H, J=5.4Hz), 7.62 (dd, 2H, J=5.7, 8.7 Hz), 7.35 (m, 3H), 7.23 (t, 2H, J=8.7 Hz),7.15 (t, 2H, J=-8.7 Hz), 6.91 (t, 2H, J=6.9 Hz), 6.62 (d, 1H, J=5.7 Hz),6.41 (s, 1H), 4.51 (d, 2H, J 5.7 Hz). MS (ES+ve): 428 (40, M⁺), 430 (30,M+3), 125 (100).

Example 32N¹-4-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyridinyl-1,3-propanediamine

[0387]

[0388] In a similar manner as described in Example 28, using1,3-diaminopropane in place of histamine, was obtained the titlecompound. ¹H NMR (CD₂Cl₂) δ 8.55 (d, 1H, J=5.4 Hz), 8.08 (d, 1H, J=3.9Hz), 7.69(m, 3H), 7.25 (dd, 1H, J=5.7, 8.7), 7.12(t, 2H, J=6.6 Hz),6.9(t, 1H, J=6.9 Hz), 6.59(d, 1H, J=5.7 Hz), 6.4(s, 1H), 5.02(m, 1H),3.33(q, 2H, J=5.1 Hz), 2.82(t, 2H, J=5.4 Hz), 1.72(n, 2H, J=5.4 Hz). MS(ES+ve): 362 (100, M⁺).

Example 333-(2-Butoxy-4-pyridinyl)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine

[0389]

[0390] In a similar manner as described in Example 28, using 1-butanolin place of histamine, was obtained the title compound. ¹H NMR(acetone-d₆) δ 8.70 (d, 1H, J=7.2 Hz), 8.16 (d, 1H, J=5.4 Hz), 7.76 (d,1H, J=9.0 Hz), 7.68. (m, 2H), 7.40 (dd, 1H, J=6.9, 8.7 Hz), 7.23 (m,2H), 7.06 (dt, 1H, J=6.9, 1.2 Hz), 6.80 (dd, 1H, J=5.4, 1.5 Hz), 6.77(s, 1H), 4.36(t, 2H, J=6.6 Hz), 1.77(quint, 2H, J=3.9 Hz), 1.5 (sext,2H, J=7.5 Hz), 1.0 (t, 3H, J=7.5 Hz). MS (ES+ve): 362 (40, M⁺), 306(100).

Example 344-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-hexyl-2-pyridinamine

[0391]

[0392] In a similar manner as described in Example 28, using hexylaminein place of histamine, was obtained the title compound. ¹H NMR(acetone-d₆) δ 8.67 (d, 1H, J=7.2 Hz), 8.05 (d, 1H, J=5.4 Hz), 7.72 (m,3H), 7.33 (dd, 1H, J=7.2, 8.4 Hz), 7.21 (t, 2H, J=9.0 Hz), 7.00 (td, 1H,J=6.9, 0.9 Hz), 6.50 (s, 1H), 6.49 (d, 1H, J=5.1 Hz), 5.85 (t, 1H, J=5.1Hz), 3.34 (quart, 2H, J=6.0 Hz), 1.61 (quint, 2H, J=6.9 Hz), 1.36 (m,6H), 0.92 (t, 3H, J=2.4 Hz). MS (ES+ve): 389 (100, M⁺).

Example 354-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(4-methoxybenzyl)-2-pyridinamine

[0393]

[0394] In a similar manner as described in Example 28, using4-methoxybenzylamine in place of histamine, was obtained the titlecompound. ¹H NMR (d₆ DMSO) δ 8.79 (d, 1H, J=7.2 Hz), 7.98 (d, 1H, J=5.4Hz), 7.62 (dd, 2H, J=5.4, 8.4 Hz), 7.53 (d, 1H, J=9.0 Hz), 7.29 (m, 5H),7.04 (quart, 2H, J=5.7 Hz), 6.92 (d, 2H, J=8.7 Hz), 6.51 (s, 1H), 6.38(d, 1H, J=5.1 Hz).

Example 364-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-pentyl-2-pyridinamine

[0395]

[0396] In a similar manner as described in Example 28, using pentylaminein place of histamine, was obtained the title compound. ¹H NMR(acetone-d₆) δ 8.66 (d, 1H, J=6.9 Hz), 8.05 (d, 1H, J=5.1 Hz), 7.73 (m,3H), 7.65 (t, 2H, J=9.0 Hz), 7.22 (t, 2H, J=2.1 Hz), 7.02 (td, 1H,J=6.9, 1.2 Hz), 6.51 (s, 1H), 6.50 (d, 1H, J=5.4 Hz), 5.82 (m, 1H), 3.34(quart, 2H, J=6.3 Hz), 1.63 (quint, 2H, J=6.9 Hz), 1.39 (m, 4H), 0.94(t, 3H, J=6.3 Hz).

Example 374-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-pyridinylmethyl)-2-pyridinamine

[0397]

[0398] In a similar manner as described in Example 28, using3-(aminomethyl)pyridine in place of histamine, was obtained the titlecompound. ¹H NMR (acetone-d₆) δ 8.50 (d, H, J=6.8 Hz), 8.32 (d, H, J=4.0Hz), 7.90 (d, H, J=5.2 Hz), 7.63 (d, H, J=7.6 Hz), 7.52 (m, H), 7.46 (d,H, J=9.2 Hz), 7.16 (m, H), 7.04 (t, H, J=8.8 Hz), 6.85 (t, H, J=6.4 Hz),6.45 (s, H), 6.37 (d, H, J=4.4 Hz). MS (ES+ve): 396 (60, M⁺), 109 (100).

Example 384-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propyl-2-pyridinamine

[0399]

[0400] In a similar manner as described in Example 28, using propylaminein place of histamine, was obtained the title compound. ¹H NMR(acetone-d₆) δ 8.67 (d, 1H, J=7.2 Hz), 8.05 (d, 1H, J=5.1 Hz), 7.72 (m,3H), 7.35 (dd, 1H, J=6.9, 9.0 Hz), 7.22 (t, 2H, J=9.0 Hz), 7.03 (t, 1H,J=6.6 Hz), 6.51 (s, 1H), 6.50 (d, H, J=7.2 Hz), 5.84 (m, 1H), 3.31(quart, 2H, J=6.6 Hz), 1.63 (sext, 2H, J=7.2 Hz), 0.98 (t, 3H, J=Hz). MS(ES+ve): 347 (100, M⁺).

Example 394-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-phenyl-2-pyridinamine

[0401]

[0402] In a similar manner as described in Example 28, using aniline inplace of histamine, was obtained the title compound. ¹H NMR (acetone-d₆)δ 8.70 (d, 1H, J=6.9 Hz), 8.32 (s, 1H), 8.24 (d, 1H, J=5.4 Hz), 7.80 (d,1H, J=9.0 Hz), 7.73 (m, 3H), 7.67 (d, 1H, J=8.1 Hz), 7.40 (dd, 1H,J=6.9, 8.4 Hz), 7.26 (m, 4H), 7.06 (dt, 1H, J=6.9, 1.2 Hz), 6.95 (t, 1H,J=7.5 Hz), 6.90 (s, 1H), 6.79 (dd, 1H, J=5.4, 1.5 Hz). MS(ES+ve): 381(100, M⁺).

Example 40N¹-4-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyridinyl-1,4-butanediamine

[0403]

[0404] In a similar manner as described in Example 28, using1,4-diaminobutane in place of histamine, was obtained the titlecompound. ¹H NMR (acetone-d₆) δ 8.66 (d, 1H, J=6.9 Hz), 8.04 (d, 1H,J=5.1 Hz), 7.72 (m, 3H), 7.34 (dd, 1H, J=6.6, 9.0 Hz), 7.21 (t, 2H,J=8.7 Hz), 7.01 (t, 1H, J=6.9 Hz), 6.53 (s, 1H), 6.49 (d, 1H, J=4.2 Hz),6.01 (t, 1H, J=5.1 Hz), 3.34 (m, 2H), 2.23 (m, 2H), 2.10 (m, 2H), 1.70(m, 2H).

Example 412-(4-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyridinylamino)-1-ethanol

[0405]

[0406] In a similar manner as described in Example 28, using2-hydroxyethylamine in place of histamine, was obtained the titlecompound. ¹H NMR (d₆ DMSO) δ 8.79 (d, 1H, J=6.9 Hz), 7.96 (d, 1H, J=5.4Hz), 7.69 (d, 1H, J=9.0 Hz), 7.62 (m, 2H), 7.36 (dd, 1H, J=8.7, 6.9 Hz),7.29 (m, 2H), 7.03 (t, 1H, J=6.6 Hz), 6.56 (m, 2H), 6.36 (d, 1H, J=5.1Hz), 3.53 (t, 2H, J=5.7 Hz), 3.34 (m, 2H). MS (ES+ve): 349 (100, M+). MS(ES+ve): 437 (100, M⁺).

Example 42N-Benzyl-4-[2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyridinamine

[0407]

[0408] In a similar manner as described in Example 28, using benzylaminein place of histamine, was obtained the title compound. ¹H NMR(acetone-d₆) δ 8.65 (d, 1H, J=6.9 Hz), 8.06 (d, 1H, J=5.1 Hz), 7.70 (m,2H), 7.54 (d, 1H, J=8.7 Hz), 7.31 (m, 7H), 7.01 (t, 1H, J=6.9 Hz), 6.58(s, 1H), 6.51 (dd, 1H, J=1.5, 5.1 Hz), 6.38 (m, 1H), 4.62 (m, 2H). MS(ES+ve): 395 (100, M⁺).

Example 434-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-dimethyl-2-pyridinamine

[0409]

[0410] In a similar manner as described in Example 28, usingN,N-dimethylamine in place of histamine, was obtained the titlecompound. ¹H NMR (CD₂Cl₂) δ 8.55(d, 1H, J=9.3 Hz), 8.17 (d, 1H, J=6.5Hz), 7.64-7.74 (m, 3H), 7.25(dd, 1H, J=8, 11.5 Hz), 7.12 (t, 2H, J=11.5Hz), 6.90 (t, 1H, J=9.3 Hz), 6.57 (d, 1H, J=6.5 Hz), 6.54(s, 1H),3.06(s, 6H). MS (ES+ve): 333.2 (100, M⁺).

Example 443-(2,6-Difluoro-4-pyridinyl)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine

[0411]

[0412] A solution of 3-bromo-2-(4-fluorophenyl)-pyrazolo[1,5-a]pyridine(from Example le, 570 mg, 1.96 mmol), 2,6-difluoro-4-pyridyl-boronicacid (340 mg, 2.15 mmol) and dichlorobis(triphenylphosphine)palladium(137 mg, 0.196 mmol) in DMF (10.0 mL) was placed in a pre-heated oilbath at 110° C. To the reaction was added, in a dropwise manner, 2Msodium carbonate (2.00 mL, 4.00 mmol). The reaction was allowed to stirfor 45 min before cooling to room temperature and filtering through aCelite 545 pad. The Celite filter was washed with ethyl acetate and thefiltrate was concentrated to dryness at 50° C. under vacuum. The residuewas dissolved in methylene chloride and dried (MgSO₄). The drying agentwas removed by filtration and the filtrate was concentrated and purifiedby silica gel chromatography to yield the title compound (160 mg, 0.492mmol, 25%). ¹H NMR (CDCl₃) δ 8.53(d, 1H, J=6.8 Hz), 7.67(d, 1H, J=8.8Hz), 7.53(dd, 2H, J=5.6, 8.0 Hz), 7.31(t, 1H, J=7.6 Hz), 7.11(t, 2H,J=8.4 Hz), 6.93(t, 1H, J=6.8 Hz), 6.75(s, 2H). MS (ES+ve): 326 (90, M⁺).

Example 45N-Benzyl-6-fluoro-4-[2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyridinamine

[0413]

[0414] In a sealed-tube was combined3-(2,6-difluoro-4-pyridinyl)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine(Example 44, 35 mg, 0.11 mmol) and benzylamine (3.0 mL, 2.9 g, 27 mmol),and the reaction was placed in a preheated oil bath at 130° C. Thereaction was stirred at 130° C. until consumption of starting materialwas indicated by TLC analysis (50% ethyl acetate in hexanes). Thecontents of the sealed-tube was transferred to a flask and concentratedto dryness at 50° C. under high vacuum. The residue was purified bysilica gel chromatography to yield the title compound, 18 mg (0.04 mmol,36%). ¹H NMR (d₆-acetone) δ 8.67(d, 1H, J=6.8 Hz), 7.71(dd, 2H, J=5.6,8.8 Hz), 7.59(d, 1H, J=8.8 Hz), 7.30-7.45(m, 6H), 7.24(t, 2H, J=8.8 Hz),7.05 (t, 1H, J=6.8 Hz), 6.73 (br t, 1H, J=6.0 Hz), 6.46 (s, 1H), 6.09(s, 1H), 4.59(d, 2H, J=6.0 Hz). MS (ES+ve): 413.1 (100, M⁺).

Example 462-(4-Fluorophenyl)-3-(2-fluoro-4-pyridinyl)-6-trifluoromethylpyrazolo[1,5-a]pyridine

[0415]

[0416] a) 2-Fluoropyridin-4-ylboronic Acid

[0417] To a stirred solution of n-butyl lithium (3.2 mL, 2.5M, 8.0 mmol)in dry diethyl ether (20 mL) at −78° C. was added a solution of2-fluoro-4-iodopyridine (1.5 g, 6.7 mmol) in dry ether (10 mL) and thereaction mixture was stirred at −78° C. for 10 min. Tributyl borate (2.4mL, 2.01 g, 8.7 mmol) was added and the reaction mixture was allowed tostir to room temperature over 2 h. Water (5 mL) was added followed by 2Naqueous sodium hydroxide solution (10 mL) to dissolve the solids. Theorganic phase was separated. The aqueous phase was acidified to pH 3using 6N HCl and the resulting white solid was collected by filtrationand dried under vacuum to give the title compound, 0.74 g (78%). 1H NMR(d₆ DMSO) δ 8.65 (br s, 2H), 8.21 (d, 1H, J=4.8 Hz), 7.59 (t, 1H, J=4.8Hz), 7.37 (d, 1H, J=1.8 Hz).

[0418] b)2-(4-Fluorophenyl)-3-(2-fluoro-4-pyridinyl)-6-trifluoromethylpyrazolo[1,5-a]pyridine

[0419] In a similar manner as described in Example 27, from2-fluoro-4-pyridylboronic acid and3-bromo-2-(4-fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridine(intermediate from Example 23) was obtained the title compound. ¹H NMR(CDCl₃) δ 8.85(s, 1H,), 8.22 (d, 1H, J=5.2 Hz), 7.70 (d, 1H, J=9.6 Hz),7.52(dd, 2H, J=5.2, 8.4 Hz), 7.38(d, 1H, 9.6 Hz), 7.09(t, 2H, J=8.4 Hz),6.90(s, 1H). MS (ES+ve): 376 (100, M⁺).

Example 474-[2-(4-Fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridin-3-yl]-N-isopropyl-2-pyridinamine

[0420]

[0421] In a similar manner as described in Example 28 using2-(4-fluorophenyl)-3-(2-fluoro-4-pyridinyl)-6-trifluoromethylpyrazolo[1,5-a]pyridine(Example 46) and isopropylamine was obtained the title compound. ¹H NMR(d₆-acetone) δ 9.12 (s, 1H), 8.04 (d, 1H, J=5.1 Hz), 7.85 (d, 1H, J=9.3Hz), 7.70 (dd, 2H, J=5.4, 8.7 Hz), 7.50(d, 1H, J=9.3 Hz), 7.21(t, 2H,J=8.7 Hz), 6.49(s, 1H), 6.45(d, 1H, J=5.1 Hz), 5.63(brd, 1H), 4.04(m,1H), 1.20 (d, 6H, J=4.8 Hz). MS (ES+ve): 415 (100, M⁺).

Example 48N-Cyclopropyl-4-[2-(4-fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridin-3-yl]-2-pyridinamine

[0422]

[0423] In a similar manner as described in Example 28 using2-(4-fluorophenyl)-3-(2-fluoro-4-pyridinyl)-6-trifluoromethylpyrazolo[1,5-a]pyridine(Example 46) and cyclopropylamine was obtained the title compound. ¹HNMR (d₆ DMSO) δ9.13 (s, 1H), 7.72(d, 1H, J=5.1 Hz), 7.55(d, 1H, J=9.3Hz), 7.27(m, 3H), 6.99(t, 2H, J=9 Hz), 6.54(s, 1H), 6.21(d, 1H, J=5.1Hz), 6.21(s, 1H), 2.05(m, 1H), 0.23(m, 2H), 0.02(m, 2H). MS (ES+ve): 413(75%, M⁺).

Example 493-(4-[2-(4-Fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]-pyridin-3-yl]-2-pyridinylamino)-1-propanol

[0424]

[0425] In a similar manner as described in Example 28 using2-(4-fluorophenyl)-3-(2-fluoro-4-pyridinyl)-6-trifluoromethylpyrazolo[1,5-a]pyridine(Example 46) and 3-hydroxypropylamine was obtained the title compound.¹H NMR (d₆-DMSO) δ 9.41(s, 1H), 7.95(d, 1H, J=5.2 Hz), 7.78(d, 1H, 9.2Hz), 7.58(dd, 2H, J=5.6, 8.8 Hz), 7.50(d, 1H, J=9.6 Hz), 7.26(t, 2H,J=8.8 Hz), 6.544(br t, 1H, J=5.6 Hz), 6.42(s, 1H), 6.33(d, 1H, J=5.6Hz), 6.46(m, 1H), 3.43(m, 2H), 3.22(br q, 2H, J=6.8 Hz), 1.62(quint, 2H,J=6.4 Hz). MS (ES+ve): 431(100, M⁺).

Example 506-Bromo-2-(4-fluorophenyl)-3-(2-fluoro-4-pyridinyl)pyrazolo[1,5-a]pyridine

[0426]

[0427] To a solution of2-(4-fluorophenyl)-3-(2-fluoro-4-pyridinyl)pyrazolo[1,5-a]pyridine(Example 27. 937 mg, 3.05 mmol) in DMF (20 mL) was addedN-bromosuccinimide (651 mg, 3.66 mmol). The reaction mixture was heatedat 60° C. for about 5 h and then allowed to cool to room temperature.Saturated sodium bicarbonate was added and the mixture was extractedwith dichloromethane. The organic extracts were dried (MgSO₄) and thesolvents removed under vacuum. The residue was purified by silica gelchromatography to give the title compound. 0.604 g (50%). ¹H NMR (CDCl₃)δ 8.68 (s, 1H), 8.20 (d, 1H, J=5.4 Hz), 7.53 (m, 3H), 7.35 (dd, 1H,J=9.3, 1.2 Hz), 7.10 (m, 3H), 7.00 (s, 1H). MS (ES+ve) 387 (50, M⁺,M+3).

Example 51N-(3-Aminopropyl)-4-[6-bromo-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyridinamine

[0428]

[0429] In a similar manner as described in Example 28, using6-bromo-2-(4-fluorophenyl)-3-(2-fluoro-4-pyridinyl)pyrazolo[1,5-a]pyridine(Example 50) and 1,3-diaminopropane was obtained the title compound. ¹HNMR (d₆-acetone) δ 8.94 (s, 1H), 8.06 (d, 1H, J=4.8 Hz), 7.72 (m, 3H),7.44 (dd, 1H, J=1.5, 9.6 Hz), 7.23 (m, 3H), 6.51 (s 1H), 6.48 (dd, 1H,J=1.2, 6.3 Hz), 6.08 (m 1H), 3.44 (q, 2H, J=5.7 Hz), 3.31 (t, 2H, J=6.3Hz), 1.90 (quint, 2H, J=6.8 Hz). MS (ES+ve) 440 (100, M⁺, M+3)

Example 526-Cyano-2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridine

[0430]

[0431] In a similar manner as described in Examples 2a, 2b, 1d, 1e, and1f, from 3-cyanopyridine was obtained the title compound. ¹H NMR (CDCl₃)δ 8.90 (s, 1H), 8.66 (d, 2H, J=5.9 Hz), 7.66 (d, 1H, J=9.2 Hz), 7.55 (m,2H), 7.30 (m, 1H), 7.25 (m, 2H), 7.09 (t, 2H, J=8.6 Hz). MS (ES+ve): 315(5, M+2), 315 (100, M+1).

Example 532-(4-Fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridine-6-carboxamide

[0432]

[0433] A mixture of6-cyano-2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridine(Example 52. 100 mg, 0.318 mmol) and concentrated hydrochloric acid (2mL) were stirred at room temperature overnight. The mixture was dilutedwith ether, basified with 5N sodium hydroxide solution and extractedthoroughly with ethyl acetate several times. The combined organic layerswere dried (MgSO₄), filtered and evaporated to dryness. The titlecompound was isolated in 85% yield (90 mg). ¹H NMR (d₆-DMSO) δ 9.36 (s,1H), 8.60 (d, 2H, J=5.2 Hz), 8.22 (bs, 1H), 7.81 (bs, 2H), 7.67 (bs,1H), 7.58 (m, 2H), 7.28-7.37 (m, 4H). MS (ES+ve): 334 (25, M+2), 333(100, M+1).

Example 546-Cyano-2-(4-fluorophenyl)-3-(2-fluoro-4-pyridinyl)pyrazolo[1,5-a]pyridine

[0434]

[0435] In a similar manner as described in Example 27, from2-fluoro-4-pyridylboronic acid and3-bromo-6-cyano-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine (intermediatefrom Example 52) was obtained the title compound. ¹H NMR (CDCl₃) δ 8.89(s, 1H), 8.24 (d, 1H, J=5.3 Hz), 7.66 (d, 1H, J=9.3 Hz), 7.52 (m, 2H),7.33 (d, 1H, J=9.3 Hz), 7.10 (m, 3H), 6.89 (s, 1H). MS (ES+ve): 334 (10,M+2), 333 (100, M+1).

Example 556-Cyano-4-[2-(4-fluorophenyl)-pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropyl-2-pyridinamine

[0436]

[0437] In a similar manner as described in Example 28, from6-cyano-2-(4-fluorophenyl)-3-(2-fluoro-4-pyridinyl)pyrazolo[1,5-a]pyridine(Example 54) and cyclopropylamine was obtained the title compound. ¹HNMR (CDCl₃) δ 8.88 (s, 1H), 8.11 (m, 1H), 7.55-7.70 (m, 4H), 7.10 (m,2H), 7.64 (m, 2H), 5.09 (s, 1H), 2.36 (m, 1H), 0.63 (m, 2H), 0.46 (m,2H). MS (ES−ve): 369 (15, M⁺), 368 (70, M−1), 228 (100).

Example 56 2-(4-Fluorophenyl)-3-(4-pyrimidinyl)-pyrazolo[1,5-a]pyridine

[0438]

[0439] a) 1-(4-fluorophenyl)-2-(4-pyrimidinyl)-ethanone

[0440] To a stirred solution of 4-methylpyrimidine (20.64 g, 0.22 mol)and ethyl 4-fluorobenzoate (36.9 g, 0.22 mol) in dry THF (100 mL) at 0°C. under nitrogen was added lithium bis(trimethylsilyl)amide (1M in THF,440 mL, 0.44 mol) over a 2 h period. A white precipitate depositedduring the addition and this suspension was stirred at room temperatureovernight. The reaction was diluted with 100 mL of water and filtered.The filtrate was washed with water (3×) and dried. The solution wasdiluted with ethyl acetate (100 mL) and the organic phase separated. Theaqueous phase was further extracted with ethyl acetate (100 mL). Organicphases were dried (MgSO₄) and concentrated and combined with thefiltrate to give a combined yield of 47 g (98%) of product. ¹H NMR(CDCl₃) exists as a 2:1 mixture of enol:keto tautomers: 6 enol form:5.95 (s, 1H), 6.92 (dd, J=1.2, 5.7 Hz, 1H), 7.06-7.14 (m, 2H), 7.83 (dd,J=5.4, 8.7 Hz, 2H), 8.40 (d, J=5.7 Hz, 1H), 8.8 (s, 1H); keto form: 4.42(s, 2H), 7.12-7.18 (m, 2H), 7.34 (d, J=4.2 Hz, 1H), 8.06 (dd, J=5.3, 8.8Hz, 2H), 8.67 (d, J=5.1 Hz, 1H), 9.16 (s, 1H); APESI-MS m/z 215 (M−1)⁻.

[0441] b) 2-(4-Fluorophenyl)-3-(4-pyrimidinyl)-pyrazolo[1,5-a]pyridine

[0442] A solution of 1-(4-fluorophenyl)-2-(4-pyrimidinyl)-ethanone (21.6g, 0.1 mol), 1-aminopyridinium iodide (22.2 g, 0.1 mol) and potassiumcarbonate (41.4 g, 0.3 mol) in a mixture of water (300 mL) andisopropanol (300 mL) was heated and stirred at 100° C. for 16 h. Theisopropanol was removed under vacuum and the resulting aqueous phaseextracted with dichloromethane (5×200 mL). The dichloromethane extractswere combined and the solvent evaporated under reduced pressure to leavea red solid which was purified by silica gel chromatography eluting witha hexane/EtOAc to give the title compound as a yellow solid, 9.16 g(32%). ¹H NMR (d₆-DMSO) δ 7.07 (d, J=5.4 Hz, 1H), 7.14 (t, J=6.8 Hz,1H), 7.32 (t, J=8.7 Hz, 2H), 7.53 (t, J=7.8 Hz, 1H), 7.60 (dd, J=5.7,8.7 Hz, 2H), 8.40 (d, J=8.9 Hz, 1H), 8.54 (d, J=5.3 Hz, 1H), 8.83 (d,J=7.1 Hz, 1H), 9.16 (s, 1H), APESI+MS m/z 291 (M+1).

Example 572-(4-Fluorophenyl)-3-(4-(2-methylthio)pyrimidinyl)pyrazolo[1,5-a]-pyridine

[0443]

[0444] a) 1-(4-Fluorophenyl)-2-(4-(2-methylthio)pyrimidinyl)ethanone

[0445] To a stirred solution of 2-methylthio-4-methylpyrimidine (66 g,0.47 mol) and ethyl 4-fluorobenzoate (79 g, 0.47 mol) in dry THF (400mL) at 0° C. under nitrogen was added lithium bis(trimethylsilyl)amide(1N in THF, 940 mL, 0.94 mol) over a 2 h period. The solution wasstirred at ice bath temperature for 18 h. The solution was poured into2L of ice cold 0.5 N HCl. A precipitate formed which was filtered offand air dried. Second and third crops of solids were obtained as theprecipitate was washed with water. The combined precipitates wererecrystalized from acetone and water to give product as a yellow solid:117 g (95%0). ¹H NMR (CDCl₃) δ (all in enol form): 3.0 (s, 3H), 6.29 (s,1H), 7.01 (d, J=5.7 Hz, 1H), 7.48 (t, J=8.7 Hz, 2H), 8.20 (dd, J=5.4,8.8 Hz, 2H), 8.68 (d, J=5.7 Hz, 1H); APESI-MS m/z 261 (M−1)⁻.

[0446] b)2-(4-Fluorophenyl)-3-(4-(2-!methylthio)pyrimidinyl)-pyrazolo[1,5-a]pyridine

[0447] A solution of1-(4-fluorophenyl)-2-(4-(2-methylthio)pyrimidinyl)ethanone (13.0 g, 50mmol) in isopropanol (300 mL) was warmed to reflux. A solution of1-aminopyridinium iodide (14 g, 63 mmol) in water (300 mL) was treatedwith 2N NaOH (31.5 mL). This solution was added to the ketone over aperiod of 2 h while the mixture was heated at reflux. After anadditional 7 h, the isopropanol was partially evaporated under reducedpressure and the resulting solution was extracted with dichloromethane(2×300 mL). The dichloromethane extracts were combined, dried (MgSO₄),filtered and the solvent evaporated under reduced pressure to leave ared solid which was purified by silica gel chromatography withdichloromethane to give the title compound as a yellow solid, 4.5 g(26%). ¹H NMR (d₆-DMSO) δ 2.5 (s, 3H), 6.80 (d, J=5.3 Hz, 1H), 7.18 (t,J=6.9 Hz, 1H), 7.36 (t, J=8.8 Hz, 2H), 7.59 (t, J=7.9 Hz, 1H), 7.60 (dd,J=5.7, 8.7 Hz, 2H), 8.38 (d, J=9.1 Hz, 1H), 8.40 (d, J=5.3 Hz, 1H), 8.88(d, J=7.0 Hz, 1H), APESI+MS m/z 337 (M+1).

Example 582-(4-Fluorophenyl)-3-(4-(2-methylsulfinyl)pyrimidinyl)pyrazolo[1,5-a]-pyridine

[0448]

[0449] To a stirred solution of2-(4-fluorophenyl)-3-(4-(2-methylthio)pyrimidinyl)pyrazolo[1,5-a]pyridine(Example 57. 0.285 g, 0.85 mmol) in dichloromethane (10 mL) was added,dropwise, a solution of (0.257 g, 0.85-1.23 mmol) of 57-86%m-chloroperoxybenzoic acid in dichloromethane (5 mL). After 10 min., thesolution was quenched by the addition of aqueous potassium carbonate (20mL), and the organic phase was separated. The aqueous phase was furtherextracted with dichloromethane (2×20 mL) and the dichloromethane phasesdried (MgSO₄) and concentrated to give a crude white solid.Chromatography on silica gel eluting with a hexane/EtOAc gradient(0-100% EtOAc) gave the title compound as a white solid, 0.213 g (60: ¹HNMR (CDCl₃) δ 3.05 (s, 3H), 7.07-7.11 (m, 2H), 7.25 (d, J=8.5 Hz, 2H),7.55 (t, J=7.8 Hz, 1H), 7.64 (dd, J=5.5, 6.9 Hz, 2H), 8.52 (d, J=5.1 Hz,1H), 8.59 (d, J=6.9 Hz, 1H), 8.84 (d, J=9.0 Hz, 1H); APESI+MS m/z 353(M+1)⁻.

Example 592-(4-Fluorophenyl)-3-(4-(2-methylsulfonyl)pyrimidinyl)pyrazolo[1,5-a]-pyridine

[0450]

[0451] Obtained as a minor product in Example 58. ¹H NMR (CDCl₃) δ 3.42(s, 3H), 7.11 (t, J=7 Hz, 1H), 7.18 (d, J=5.5 Hz, 1H), 7.26 (t, J=8.6Hz, 2H) overlapping with CHCl₃, 7.58 (t, J=8.0 Hz, 1H), 7.64 (dd, J=5.5,8.5 Hz, 2H), 8.53 (d, J=5.5 Hz, 1H), 8.60 (d, J=6.8 Hz, 1H), 8.78 (d,J=8.8 Hz, 1H); APESI+MS m/z 369 (M+1)⁻.

Example 60N-Butyl-4-[2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidin-amine

[0452]

[0453] A solution of2-(4-fluorophenyl)-3-(4-(2-methylsulfinyl)pyrimidinyl)pyrazolo[1,5-a]pyridine(Example 58. 0.03 g, 0.085 mmol) in n-butylamine (0.5 mL) was heated toreflux for 0.25 h. On cooling a white solid deposits which was collectedby filtration, washed with hexane and dried under vacuum to give thetitle compound as a white solid, 0.029 g (94%). ¹H NMR (d₆-DMSO) δ 0.87(t, J=7.4 Hz, 3H), 1.31 (sextet, J=7.4 Hz, 2H), 1.49(quintet, J=7.2 Hz,2H), 3.25 (q, J=6.6 Hz, 2H), 6.4 (bs, 1H), 7.06 (t, J=6.8 HZ, 1H), 7.13(bs, 1H), 7.29 (t, J=8.8 Hz, 2H), 7.43 (t, J=7.8 Hz, 1H), 7.59 (dd,J=5.7, 8.5 Hz, 2H), 8.01 (d, J=5.3 Hz, 1H), 8.40 (bs, 1H), 8.76 (d,J=6.9 Hz, 1H); APESI+MS m/z 362 (M+1)⁻.

Example 61N-Cyclopropyl-4-[2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

[0454]

[0455] In a similar manner as described for Example 60, from2-(4-fluorophenyl)-3-(4-2-methylsulfinyl)pyrimidinyl)pyrazolo[1,5-a]pyridine(Example 58. 0.05 g, 0.14 mmol) and cyclopropylamine was obtained thetitle compound as a white solid, 0.018 g. (60%). ¹H NMR (CDCl₃) δ0.65-0.70 (m, 2H), δ 0.89-0.95 (m, 2H), δ 2.85-2.92 (m, 1H), 5.47 (bs,1H), 6.42 (d, J=5.4 Hz, 1H), 6.96 (t, J=6.2 Hz, 1H), 7.19 (t, J=8.6 Hz,2H), 7.36 (t, J=7.3 Hz, 1H), 7.66 (dd, J=5.4, 8.7 Hz, 2H), 8.12 (d,J=5.4 Hz, 1H), 8.54 (d, J=7.0 Hz, 1H), 8.62 (d, J=9.0 Hz, 1H); APESI+MSm/z 346 (M+1)⁻.

Example 62N-Benzyl-4-[2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

[0456]

[0457] In a similar manner as described for Example 60, from2-(4-fluorophenyl)-3-(4-(2-methylsulfinyl)pyrimidinyl)pyrazolo[1,5-a]pyridine(Example 58. 0.03 g, 0.085 mmol) and benzylamine was obtained the titlecompound as a white solid, 0.027 g. (60%). ¹H NMR (d₆-DMSO) δ 4.52 (d,J=6.3 Hz, 2H), 6.17 (d, J=5.2 Hz, 1H), 7.00 (bs, 1H), 7.18-7.34 (m, 9H),7.54-7.62 (m, 2H), 7.74 (t, J=6.0 Hz, 1H), 8.04 (d, J=5.1 Hz, 1H), 8.72(d, J=5.8 Hz, 1H); APESI+MS m/z 396 (M+1)⁻

Example 634-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl-N-(2-propyl)-2-pyrimidinamine

[0458]

[0459] In a similar manner as described for Example 60, from2-(4-fluorophenyl)-3-(4-(2-methylsulfinyl)pyrimidinyl)pyrazolo[1,5-a]pyridine(Example 58. 0.063 g, 0.18 mmol) and isopropylamine was obtained thetitle compound as a white solid, 0.022 g (66%). ¹H NMR (CDCl₃) δ 1.28(d, J=6.6 Hz, 6H), δ 4.21 (septet, J=6.6 Hz, 1H), δ 5.02 (bs, 1H), 6.29(d, J=5.3 Hz, 1H), 6.89 (t, J=6.4 Hz, 1H), 7.12 (t, J=8.6 Hz, 2H), 7.31(t, J=7.9 Hz, 1H), 7.60 (dd, J=5.5, 8.6 Hz, 2H), 8.03 (d, J=5.3 Hz, 1H),8.38 (d, J=8.9 Hz, 1H), 8.48 (d, J=7.0 Hz, 1H); APESI+MS m/z 348 (M+1)⁻.

Example 644-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

[0460]

[0461] a) 2-(4-Fluorophenyl)-3-acetylpyrazolo[1,5-a]pyridine

[0462] A mixture of 2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine (2.00 g,9.42 mmol) in acetic anhydride (20 mL) and conc. H₂SO₄ (2 drops) wasstirred and heated at reflux for 30 min. The mixture was cooled to roomtemperature, poured into ice water (300 mL), and basified (pH=10) using1N NaOH(aq). The resulting orange precipitate was collected byfiltration, washed with water, air-dried, then dried under high-vacuumto afford the title compound as an orange solid, 2.60 g (quant.). ¹H NMR(CDCl₃) δ 8.56 (d, 1H, J=6.9 Hz), 8.45 (d, 1H, J=9.3 Hz), 7.62 (m, 2H),7.54 (m, 1H), 7.24 (m, 2H), 7.08 (m, 1H), 2.20 (s, 3H): MS (+ve ionelectrospray) 255 (100), (MH+).

[0463] b)2-(4-Fluorophenyl)-3-(3-(dimethylamino)-2-propenoyl)pyrazolo[1,5-a]pyridine

[0464] A mixture of 2-(4-fluorophenyl)-3-acetylpyrazolo[1,5-a]pyridine(1.0 g, 3.93 mmol) in N,N-dimethylformamide dimethyl acetal (10 mL) wasstirred and heated at reflux for 17 h. The mixture was cooled to roomtemperature and the volatiles evaporated under reduced pressure. Theresidue was purified by silica gel chromatography (eluded with 1%MeOH/CH₂Cl₂) to afford the title compound as an orange solid, 0.830 g(68%). ¹H NMR (CDCl₃) 88.50 (d, 1H, J=6.9 Hz), 8.39 (d, 1H, J=9.0 Hz),7.83 (d, 2H, J=12.6 Hz), 7.73 (m, 2H), 7.39 (m, 1H), 7.20 (m, 2H), 6.93(m, 1H), 5.13 (d, 1H, J=12.5 Hz), 3.10 (s. 3H), 2.56 (s, 3H). MS (+veion electrospray) 310 (90), (MH+).

[0465] c)4-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

[0466] A mixture of2-(4-fluorophenyl)-3-(3-(dimethylamino)-2-propenoyl)pyrazolo[1,5-a]pyridine(60 mg, 0.19 mmol), guanidinium hydrochloride (36 mg, 0.38 mmol), andK₂CO₃ (105 mg, 0.76 mmol) in N,N-dimethylformamide (3 mL) was stirred ina 110° C. oil bath for 8 h. Additional guanidinium hydrochloride (36 mg,0.38 mmol) was added, and the mixture stirred in a 110° C. oil bath for16 h. The mixture was cooled to room temperature, and water (20 mL)added. The resulting tan precipitate was collected by filtration, washedwith water, air-dried, the dried under high-vacuum to afford the titlecompound, 0.033 g (57%). ¹H NMR (CDCl₃) δ 8.57 (d, 1H, J=6.0 Hz), 8.51(d, 1H, J=8.9 Hz), 7.98 (d, 2H, J=5.7 Hz), 7.64 (m, 2H), 7.46 (m, 1H),7.22 (m, 2H), 7.04 (m, 1H), 6.47 (d, 1H, J=5.8 Hz), 5.76 (s. 2H). MS(+ve ion electrospray) 306 (100), (MH+).

Example 654-[2-(4-Fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

[0467]

[0468] a) 1-(4-Fluorophenyl)-2-(2-(5-trifluoromethyl)pyridyl)ethanone

[0469] To a solution of 4-fluoroacetophenone (13.8 g, 0.100 mol) and2-chloro-5-trifluoromethylpyridine (20.0 g, 0.110 mol) intetrahydrofuran (400 mL) was added sodium hydride (95%, 5.56 g, 0.220mol) in several portions. The reaction was stirred at room temperaturefor 72 h then carefully quenched by the addition of water (300 mL) anddiethyl ether (200 mL). The organic layer was separated and extractedwith 6N HCl (2×300 mL). The aqueous extracts were cooled to 0° C. and 6NNaOH was used to adjust the solution to pH 12. The mixture was thenextracted with diethyl ether and the combined organic extracts weredried (MgSO₄). The drying agent was removed by filtration and thefiltrate was evaporated to dryness to afford the title compound as atautomeric mixture, 20.9 g (73%). ¹H NMR (CDCl₃) δ 81.87 (s), 8.63 (s),8.14 (dd, J=5.1, 8.4 Hz), 8.00-7.83(m), 7.51(d, J=8.4 Hz), 7.22-7.12(m),6.13(s), 4.60(s). MS (ES+ve): 284 (100, M⁺+1).

[0470] b) 1-(4-Fluorophenyl)-2-(2-(5-trifluoromethyl)pyridyl)ethanoneOxime

[0471] To a solution of1-(4-fluorophenyl)-2-(2-(5-trifluoromethyl)pyridyl)ethanone (80.0 g,0.282 mol) in methanol (1 L) at room temperature was added 10% aqueoussodium hydroxide (436 mL, 1.09 mol). The resulting solution was stirredvigorously as solid hydroxylamine hydrochloride (98.0 g, 1.40 mol) wasadded. The mixture was heated to reflux for 2 h, treated withdecolorizing charcoal while hot, then filtered through Celite while hot.The filtrate was concentrated to one-half its original volume and thencooled to 0° C. with stirring for 1 h. The resulting solids werecollected by filtration, washed with water, and dried under vacuum at50° C. overnight to provide the title compound as a light yellow powder,73.9 g (88%). ¹H NMR (d₆-DMSO) δ 11.60 (s, 1H), 8.86 (s, 1H), 8.14 (dd,1H, J=2.1, 8.1 Hz), 7.78 (dd, 2H, J=5.7, 9.0 Hz), 7.53 (d, 1H, J=8.4Hz), 7.23 (t, 2H, J=9.0 Hz), 4.40 (s, 2H). MS (ES+ve): 299 (70, M⁺+1).

[0472] c) 3-(4-Fluorophenyl)-2-(2-(5-trifluoromethyl)pyridyl)-2H-azirine

[0473] To a solution of1-(4-fluorophenyl)-2-(2-(5-trifluoromethyl)pyridyl)ethanone oxime (25.0g, 0.084 mol) in methylene chloride (400 mL) was added triethylamine(46.7 mL, 0.335 mol). The solution was cooled to 0° C. under a nitrogenatmosphere, and trifluoroacetic anhydride (140.1 mL, 0.100 mol) wasadded dropwise. The reaction was stirred for 0.5 h then quenched withwater. The organic layer was separated and dried (MgSO₄). The dryingagent was removed by filtration and the solvent was evaporated from thefiltrate to leave an oil. The residue was loaded onto a silica gelcolumn and eluted with 0.15% ethyl acetate in hexanes to give the titlecompound as an oil which solidified on standing, 19.4 g (82%). ¹H NMR(CDCl₃) δ 876 (s, 1H), 7.93(dd, 2H, J=5.4, 8.7 Hz), 7.83(dd, 1H, J=2.1,8.4 Hz), 7.27(t, 2H, J=8.7 Hz), 7.21(d, 1H, J=8.1 Hz), 3.54 (s, 1H). MS(ES+ve): 281 (100, M⁺+1).

[0474] d) 2-(4-Fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridine

[0475] 3-(4-Fluorophenyl)-2-(2-(5-trifluoromethyl)pyridyl)-2H-azirine(40.0 g, 0.143 mol) was dissolved in 1,2,4-trichlorobenzene (400 mL) andthe mixture was heated to 200° C. for 10 h. The reaction mixture wasthen cooled to room temperature and poured onto a silica gel column. Thecolumn was eluted with hexanes to remove the 1,2,4-trichlorobenzene, andthen with 20% diethyl ether in hexanes to elute the product. The desiredfractions were combined and the solvent was evaporated under reducedpressure to leave the title compound, 28.7 g (71%). ¹H NMR (CDCl₃) δ884(s, 1H), 7.98(dd, 2H, J=5.4, 8.7 Hz), 7.65(d, 1H, J=9.3 Hz), 7.28(d,1H, J=9.3 Hz), 7.20(t, 2H, J=8.7 Hz), 6.88(s, 1H). MS (ES+ve): 281 (100,M⁺+1).

[0476] e)2-(4-Fluorophenyl)-3-acetyl-6-trifluoromethylpyrazolo[1,5-a]pyridine

[0477] To a mixture of2-(4-fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridine (10.30 g,36.76 mmol) and acetic anhydride (100 mL) was added conc. sulfuric acid(10 drops) and the mixture was stirred and heated at reflux for 1 h. Thereaction mixture was cooled to room temperature and poured into icewater (300 mL). 2N Aqueous sodium hydroxide solution was added to raisethe pH of the solution to about 10 and the resulting orange precipitatewas collected by filtration. The solid was washed with water, air-dried,and then dried under vacuum to afford the title compound as an orangesolid, 11.87 g (quant.). ¹H NMR (d₆-DMSO) δ 9.58 (s, 1H), 8.41 (d, 1H,J=9.3 Hz), 7.89 (d, 1H, J=9.5 Hz), 7.74 (m, 2H), 7.39 (m, 2H), 2.22 (s,3H). MS (+ve ion electrospray) 323 (70), (MH+).

[0478] f)2-(4-fluorophenyl)-3-(3-(dimethylamino)-2-propenoyl)-6-trifluoromethylpyrazolo[1,5-a]pyridine

[0479] A mixture of2-(4-fluorophenyl)-3-acetyl-6-trifluoromethylpyrazolo[1,5-a]pyridine(11.85 g, 36.77 mmol) and N,N-dimethylformamide dimethyl acetal (100 mL)was stirred at reflux for 17 h. The mixture was cooled to roomtemperature and then to 0° C. The resulting orange precipitate wascollected by filtration, washed with cold hexanes, and dried undervacuum to afford the title compound as an orange solid, 10.17 g (73%).¹H NMR (d₆-DMSO) δ 9.44 (s, 1H), 8.22 (d, 1H, J=9.4 Hz), 7.75 (m, 2H),7.65 (d, 1H, J=9.5 Hz), 7.56 (d, 1H, J=12.4 Hz), 7.35 (m, 2H), 5.05 (d,1H, J=12.3 Hz), 3.04 (s, 3H), 2.56 (s, 3H). MS (+ve ion electrospray)377 (80), (M+).

[0480] g)4-[2-(4-Fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

[0481] A mixture of2-(4-fluorophenyl)-3-(3-(dimethylamino)-2-propenoyl)-6-trifluoromethylpyrazolo[1,5-a]pyridine(100 mg, 0.27 mmol), guanidinium hydrochloride (52 mg, 0.54 mmol), andsodium ethoxide (73 mg, 1.08 mmol) in EtOH (4 mL) was stirred at refluxfor 21 h. Additional guanidine was added in portions to the mixtureuntil starting material was consumed as evidenced by TLC. The reactionmixture was cooled to 0° C. and the resulting precipitate was collectedby filtration washed with cold EtOH and dried under vacuum to afford thetitle compound as a tan solid, 93 mg (92%). ¹H NMR (acetone-d₆) δ 919(s, 1H), 8.73 (d, 1H, J=9.4 Hz), 8.13 (d, 1H, J=5.2 Hz), 7.78 (m, 2H),7.63 (d, 1H, J=9.5 Hz), 7.34 (m, 2H), 6.41 (d, 1H, J=5.2 Hz), 6.17 (s,1H). MS (+ve ion electrospray) 374 (100), (MH+).

Example 66N-Butyl-4-[2-(4-fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

[0482]

[0483] In a similar manner as described for Example 65g, usingN-butylguanidine in place of guanidinium hydrochloride was obtained thetitle compound as a yellow solid, (37%). ¹H NMR (acetone-d₆) & 914 (s,1H), 8.63 (d, 1H, J=9.3 Hz), 8.09 (d, 1H, J=5.1 Hz), 7.72 (m, 2H), 7.59(d, 1H, 19.3 Hz), 7.27 (m, 2H), 6.40 (s, 1H), 6.33 (d, 1H, J=4.2 Hz),3.44 (m, 2H), 1.62 (m, 2H), 1.42 (m, 2H), 0.93 (m, 3H). MS (+ve ionelectrospray) 430 (95), (MH+).

Example 67N-Benzyl-4-[2-(4-fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

[0484]

[0485] In a similar manner as described for Example 65g, usingN-benzylguanidine in place of guanidinium hydrochloride was obtained thetitle compound as a tan solid, (quant.). ¹H NMR (acetone-d₆) δ 9109 (s,1H), 8.12 (d, 1H, J=5.1 Hz), 7.69 (m, 2H), 7.24-7.42 (m, 7H), 7.01 (m,1H), 6.34 (d, 1H, J=5.1 Hz), 4.70 (d, 2H, J=6.2 Hz). MS (+ve ionelectrospray) 464 (95), (MH+).

Example 68N-Cyclopropyl-4-[2-(4-fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

[0486]

[0487] In a similar manner as described for Example 65g, usingN-cyclopropylguanidine in place of guanidinium hydrochloride wasobtained the title compound as an off-white solid, (77%). ¹H NMR(acetone-d₆) δ 914 (s, 1H), 8.88 (s, 1H), 8.11 (d, 1H, J=5.0 Hz), 7.73(m, 2H), 7.62 (d, 1H, J=9.4 Hz), 7.30 (m, 2H), 6.62 (s, 1H), 6.37 (s,1H, J=5.1 Hz), 2.87 (m, 1H), 0.80 (m, 2H), 0.60 (m, 2H). MS (+ve ionelectrospray) 414 (100), (MH+).

Example 694-[2-(4-Fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridin-3-yl]-N-(2-propyl)-2-pyrimidinamine

[0488]

[0489] In a similar manner as described for Example 65g, usingN-isopropylguanidine in place of guanidinium hydrochloride was obtainedthe title compound as a white solid, (40%). ¹H NMR (acetone-d₆) δ 9.19(s, 1H), 8.69 (d, 1H, J=9.5 Hz), 8.15 (d, 1H, J=5.2 Hz), 7.76 (m, 2H),7.65 (d, 1H, J=9.5 Hz), 7.35 (m, 2H), 6.38 (d, 1H, J=5.2 Hz), 6.25 (s,1H), 4.27 (m, 1H), 1.31 (d, 6H, J=6.6 Hz). MS (+ve ion electrospray) 416(100), (M+).

Example 704-[2-(4-Fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridin-3-yl]-N-(2-propenyl)-2-pyrimidinamine

[0490]

[0491] In a similar manner as described for Example 65g, usingN-(2-propenyl)guanidine in place of guanidinium hydrochloride wasobtained the title compound as a white solid, (49%). ¹H NMR (acetone-d₆)δ 9.14 (s, 1H), 8.66 (d, 1H, J=9.1 Hz), 8.11 (d, 1H, J=5.2 Hz), 7.72 (m,2H), 7.59 (d, 1H, J=9.3 Hz), 7.28 (m, 2H), 6.56 (s, 1H), 6.36 (d, 1H,J=5.1 Hz), 6.03 (m, 1H), 5.27 (dd, 1H, J=18.9 Hz), 5.09 (d, 1H, J=10.4Hz), 4.09 (m, 1H). MS (+ve ion electrospray) 414 (100), (MH+).

Example 714-[2-(4-Fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridin-3-yl]-N-(2,2,2-trifluoroethyl)-2-pyrimidinamine

[0492]

[0493] In a similar manner as described for Example 65g, usingN-(2,2,2-trifluoroethyl)guanidine in place of guanidinium hydrochloridewas obtained the title compound as a white solid, (24%). ¹H NMR(acetone-d₆) δ 9.16 (s, 1H), 8.62 (s, 1H), 8.19 (d, 1H, J=5.0 Hz), 7.71(m, 2H), 7.61 (d, 1H, J=9.3 Hz), 7.28 (m, 2H), 7.03 (s, 1H), 6.51 (d,1H, J=4.0 Hz), 4.28 (m, 2H). MS (+ve ion electrospray) 456 (100), (MH+).

Example 723-(4-[2-(4-Fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinylamino)-1-propanol

[0494]

[0495] a)4-[2-(4-Fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridin-3-yl]-N-(3-(4-methoxybenzyloxy)propyl)-2-pyrimidinamine

[0496] A mixture of2-(4-fluorophenyl)-3-(3-(dimethylamino)-2-propenoyl)-6-trifluoromethyl-pyrazolo[1,5-a]pyridine(Example 65f. 2.0 g, 5.3 mmol),N-(3-(4-methoxybenzyloxy)propyl)-guanidine (2.7 g, 7.95 mmol), andpotassium carbonate (2.2 g, 15.9 mmol) was stirred inN,N-dimethylformamide (20 mL) in a 100° C. oil bath for 18 h. Themixture was cooled to room temperature, water (200 mL) was added themixture was extracted with chloroform. The chloroform extracts weredried over anhydrous MgSO₄, filtered, and the solvent was evaporated.The crude material was purified by chromatography on silica gel using30% EtOAc/hexanes as eluent to afford the title compound as a whitesolid, 2.1 g (72%). ¹H NMR (acetone-d₆) δ 9.18 (s, 1H), 8.67 (d, 1H,J=9.4 Hz), 8.15 (d, 1H, J=5.1 Hz), 7.77 (m, 2H), 7.56 (d, 1H, J=9.2 Hz),7.34 (m, 4H), 6.90 (d, 2H, J=8.6 Hz), 6.50 (s, 1H), 6.38 (d, 1H, J=5.1Hz), 4.49 (s, 2H), 3.80 (s, 3H), 3.63 (m, 4H), 1.98 (m, 2H). MS (+ve ionelectrospray) 551 (30), (M+).

[0497] b)3-(4-[2-(4-Fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinylamino)-1-propanol

[0498] A solution of4-[2-(4-fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridin-3-yl]-N-(3-(4-methoxybenzyloxy)propyl)-2-pyrimidinamine(2.1 g, 3.8 mmol) in 4N HCl/dioxane (5 mL) was stirred at roomtemperature for 4.5 h, then heated to reflux for 1 h. The mixture wascooled to room temperature, neutralized with saturated aqueous NaHCO₃,and extracted with EtOAc. The EtOAc extracts were dried (MgSO₄),filtered, and the solvent was evaporated. The residue was trituratedwith 2% EtOAc/hexanes to afford a solid which was collected byfiltration and dried to give the title compound as a white solid, 1.31 g(80% yield). ¹H NMR (acetone-d₆) 689.20 (s, 1H), 8.73 (d, 1H, J=9.3 Hz),8.15 (d, 1H, J=5.1 Hz), 7.77 (m, 2H), 7.64 (d, 1H, J=9.9 Hz), 7.34 (m,2H), 6.50 (s, 1H), 6.40 (d, 1H, J=5.1 Hz), 3.60-3.70 (m, 4H), 1.88 (m,2H). MS (+ve ion electrospray) 432 (95), (MH+).

Example 73N-Cyclopropyl-4-[6-cyano-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

[0499]

[0500] a) 2-(2-(5-Cyanopyridyl))-1-(4-fluorophenyl)ethanone

[0501] To a cooled solution (0° C.) of 6-methylnicotinonitrile (5.0 g,42 mmol) and ethyl 4-fluorobenzoate (6.2 mL, 42 mmol) in anhydroustetrahydrofuran (50 mL) under N₂ was added lithiumbis(trimethylsilyl)amide (1.0M solution in tetrahydrofuran. 84 mL, 84mmol). The reaction mixture was warmed to room temperature and wasallowed to stir at room temperature for 18 h The solvents wereevaporated under reduced pressure and the residue was triturated withether and water. The resulting solid was collected by filtration anddried in vacuo to give the title compound as a yellow solid, 10.2 g(quant.). ¹H NMR (d₆-DMSO) showed a mixture of tautomers.

[0502] b) 2-(4-Fluorophenyl)-6-cyanopyrazolo[1,5-a]pyridine

[0503] N-Boc-O-mesitylsulfonylhydroxylamine (26.7 g, 84.5 mmol) wasadded in portions to trifluoroacetic acid at 0° C. The mixture wasstirred at 0° C. for 30 min and then poured into ice water. Theresulting white precipitate was collected by filtration, washed withcold water, and dissolved in dichloromethane (300 mL). The organicsolution was dried (MgSO₄). The drying agent was removed by filtrationand the filtrate was transferred to a flask. To this solution was added2-(2-(5-cyanopyridyl))-1-(4-fluorophenyl)ethanone (6.77 g, 28.2 mmol)and the reaction mixture was stirred at room temperature for about 24 h.The reaction mixture was washed with water, dried (MgSO₄), filteredthrough a short pad of silica gel and the solvent evaporated underreduce pressure. The residue was purified using chromatography to givethe title compound as a brown solid, 2.6 g (39%). ¹H NMR (CDCl₃) δ 6.90(s, 1H), 7.15, (m, 3H), 7.57 (d, 1H, J=8.0 Hz), 7.93 (dd, 2H, J=5.2, 8.4Hz), 8.82 (s, 1H).

[0504] c) 2-(4-Fluorophenyl)-3-acetyl-6-cyanopyrazolo[1,5-a]pyridine

[0505] A solution of 2-(4-fluorophenyl)-6-cyanopyrazolo[1,5-a]pyridine(6.7 g, 11 mmol) and concentrated sulfuric acid (2 drops) in aceticanhydride (25 mL) was heated, and stirred, at 120° C. under N₂ for 5 h.The solution was cooled to room temperature, diluted with ice water andbasified to pH 11 using 2 N aqueous sodium hydroxide. The solution wasextracted with chloroform (3×), and the combined organic extracts weredried and the solvent was evaporated in vacuo. Trituration with methanolafforded a light brown solid which was collected and dried to give thetitle compound, 1.6 g (84%). ¹H NMR (d₆-DMSO) δ 2.19 (s, 3H), 7.35 (t,2H, J=8.0 Hz), 7.69 (dd, 2H, J=4.0, 8.0 Hz), 7.86 (dd, 1H, J=4.0, 16Hz), 8.30 (d, 1H, J=12 Hz), 9.75 (s, 1H). MS (ES+) m/z 280 (M⁺+H).

[0506] d)2-(4-Fluorophenyl)-3-(3-(dimethylamino)-2-propenoyl)-6-cyanopyrazolo[1,5-a]pyridine

[0507] A mixture of2-(4-fluorophenyl)-3-acetyl-6-cyanopyrazolo[1,5-a]pyridine (1.6 g, 5.6mmol) and dimethylformamide-dimethylacetal (15 mL) was stirred andheated at 130° C., under N₂, overnight. The solution was cooled and theresulting solid was collected by filtration and rinsed with acetone. Thefiltrate was evaporated and the resulting solid was purified usingchromatography. The product solids were combined to afford the titlecompound as a brown solid, 1.3 g (68%). ¹H NMR (d₆-DMSO) showed amixture of isomers. MS (ES+) m/z 335 (M⁺+H), 264 (M⁺−70).

[0508] e)N-Cyclopropyl-4-[6-cyano-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

[0509] To a solution of2-(4-fluorophenyl)-3-(3-(dimethylamino)-2-propenoyl)-6-cyanopyrazolo[1,5-a]pyridine(1.3 g, 3.9 mmol) in dimethylformamide (20 mL), under N₂, was addedN-cyclopropylguanidine (0.78 g, 7.8 mmol) and potassium carbonate (1.1g, 7.8 mmol). The mixture was stirred and heated at 100° C. for 17 h andthen additional N-cyclopropyl-guanidine (0.39 g, 3.9 mmol) and potassiumcarbonate (0.55 g, 3.9 mmol) were added. The mixture was heated at 100°C. for an additional 4 h and then the reaction mixture was cooled andwater added. The resulting solid was collected by filtration. This solidwas dissolved in diethyl ether and purified using chromatography to givethe title compound as a yellow solid, 0.39 g (28%). ¹H NMR (d₆-DMSO) δ0.50 (m, 2H), 0.69 (d, 2H, J=4.0 Hz), 2.69 (m, 1H), 6.29 (d, 1H, J=8.0Hz), 7.34 (t, 2H, J=8.0 Hz), 7.47 (d, 1H, J=4.0 Hz), 7.69 (m, 3H), 8.11(d, 1H, J=4.0 Hz), 8.56 (br 5,1H) MS (ES+) m/z 370 (M⁺+H).

Example 74N-Cyclopropyl-4-[6-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

[0510]

[0511] a) 2-(2-(5-chloropyridyl))-1-(4-fluorophenyl)ethanone

[0512] In a similar manner as described in Example 65a. From4-fluoroacetophenone and 2,5-dichloropyridine was obtained the titlecompound. ¹H NMR (d₆-DMSO) showed a mixture of tautomers. MS (ES+) m/z250 (M⁺+H), 216 (M⁺−33).

[0513] b) 2-(2-(5-Chloropyridyl))-1-(4-fluorophenyl)ethanone Oxime

[0514] In a similar manner as described in Example 65b. From2-(2-(5-chloropyridyl))-1-(4-fluorophenyl)ethanone and hydroxylaminehydrochloride was obtained the title compound. ¹H NMR (d₆-DMSO) δ 4.28(s, 2H), 7.21 (t, 2H, J=9.0 Hz), 7.33 (d, 1H, 8.4 Hz), 7.76 (dd, 2H,J=5.7, 9.0 Hz), 7.84 (dd, 1H, J=2.7, 8.4 Hz), 8.50 (d, 1H, J=2.4 Hz),11.55 (s, 1H). MS (ES+) m/z 265 (M⁺+H), 247 (M⁺−17).

[0515] c) 3-(2-(5-Chloropyridyl))-2-(4-fluorophenyl)azirine

[0516] In a similar manner as described in Example 65c. From2-(2-(5-chloropyridyl))-1-(4-fluorophenyl)ethanone oxime was obtainedthe title compound. ¹H NMR (d₆-DMSO) δ 3.49 (s, 1H), 7.36, (d, 1H, J=8.4Hz), 7.47 (t, 2H, J=8.8 Hz), 7.83 (dd, 1H, J=2.4, 8.4 Hz), 7.96 (dd, 2H,J=5.6, 8.8 Hz), 8.43 (d, 1H, J=2.4 Hz).

[0517] d) 2-(4-Fluorophenyl)-6-chloropyrazolo[1,5-a]pyridine

[0518] In a similar manner as described in Example 65d. From3-(2-(5-chloropyridyl))-2-(4-fluorophenyl)azirine was obtained the titlecompound. ¹H NMR (CDCl₃) δ 6.80 (s, 1H), 7.15, (m, 3H), 7.50 (d, 1H,J=9.3 Hz), 7.95 (dd, 2H, J=5.4, 8.7 Hz), 8.54 (s, 1H). MS (ES+) m/z 247(M⁺+H), 248 (M⁺+2).

[0519] e)N-Cyclopropyl-4-[6-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

[0520] In a similar manner as described in Example 65e and f and 73e.From 2-(4-fluorophenyl)-6-chloropyrazolo[1,5-a]pyridine was obtained thetitle compound.

Example 762-(4-Fluorophenyl)-3-(4-(2-cyclopropylamino)pyrimidinyl)-6-pyrazolo-[1,5-a]pyridinylcarboxamide

[0521]

[0522] To a solution of sodium methoxide (11.7 g, 0.217 mol) in methanol(100 mL) was addedN-cyclopropyl-4-[2-(4-fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine(Example 68. 3.0 g, 7.26 mmol) and the mixture was heated to reflux andstirred for 24 h. The reaction was cooled to room temperature and sat.aq. NH₄Cl sol was added. The resulting orange solid was collected byfiltration and dried in air to give a trimethylorthoformate product,3.25 g (99%). This orthoformate was added to a mixture of acetone (100mL) and water (10 mL) and p-toluenesulfonic acid was added. This mixturewas heated to about 40° C. for 2 h. The solution was cooled to roomtemperature and the solvent was evaporated under reduced pressure andthe residue was partitioned between water (150 mL) and ethyl acetate(150 mL). The organic phase was separated and dried (MgSO₄). The dryingagent was removed and the solvent was evaporated to leave an ester as anorange powder, 2.5 g (86%). A suspension of this ester (1.3 g, 3.23mmol) in a saturated solution of ammonia in methanol (40 mL) was placein a sealed tube and the tube was heated at about 100° C. for 24 h. Thereaction mixture was cooled to room temperature and the resultingprecipitate was collected by filtration and dried to give the titlecompound as an off white solid, 1.17 g (95%). ¹H NMR (d₆-DMSO) δ 9.33(s, 1H), 8.63 (d, 1H, J=8.3 Hz), 8.22 (s, 1H), 8.12 (d, 1H, J=4.8 Hz),7.90 (d, 1H, J=9.2 Hz), 7.69 (m, 3H), 7.4 (m, 3H), 6.27 (d, 1H, J=4.9Hz), 2.76 (m, 1H), 0.73 (d, 2H, J=4.4 Hz), 0.54 (d, 2H, J=3.3 Hz). MS(ES+ve): 389 (95%, MH³⁰).

Example 762-(4-Fluorophenyl)-3-(4-(2-(3-hydroxypropyl)amino)pyrimidinyl)-6-pyrazolo-[1,5-a]pyridinylcarboxamide

[0523]

[0524] A solution of N-(3-hydroxypropyl)guanidine (5.4 mmol) (preparedfrom O-methylisourea-hydrochloride (0.597 g, 5.4 mmol) and propanolamine(0.405 g, 5.4 mmol)) in ethanol (15 mL) was added to a solution ofsodium ethoxide (20 mmol) in ethanol (40 mL). To this mixture was addedthe enamine described in Example 65f (1.88 g, 5.0 mmol) and the reactionmixture was heated at reflux for 24 h. The solvent was evaporated underreduced pressure and the residue was partitioned between saturatedammonium chloride solution and 2:1 ethyl acetate:diethyl ether. Theorganic phase was dried (MgSO₄), filtered to remove the drying agent andthe solvents were evaporated. The resulting oil was purified by silicagel chromatography using 90% ethyl acetate in hexanes as eluent to givea pyrimidine orthoester compound 1.70 g (3.3 mmol). The orthoesterdescribed above (1.73 g, 3.40 mmol) was dissolved in acetone (200 mL)containing water (5 mL). To this solution was added p-TSA monohydrate(0.645 g, 3.40 mmol) and the reaction was stirred at room temperaturefor 30 min. The acetone was removed under reduced pressure and theresidue was dissolved in a tetrahydrofuran:ethyl ether mixture (3:1).The organic phase was washed with saturated sodium bicarbonate solution.The organic layer was dried (MgSO₄), filtered and concentrated todryness. The residue was triturated with diethyl ether and the solidswere collected by filtration to afford an ethyl ester, 0.965 g (2.20mmol) as a white solid. A mixture of the ester described above (1.46 g,2.98 mmol), sodium cyanide (15 mg, 0.30 mmol) and ammonia in methanol(30 mL, 7M solution) was stirred at room temperature for 5 days. Water(20 mL) was added and the mixture was stirred in an ice-water bath for30 min. The resulting solid was collected by filtration and dried undervacuum. The solids were then triturated with tetrahydrofuran at 50° C.for 10 min, collected by filtration and dried under vacuum to afford thetitle compound, 0.935 g (2.30 mmol, 77% yield) as a white powder. ¹HNMR-(d₆-DMSO, 80° C.): δ 9.30 (s, 1H), 8.44 (d, 1H, J=9.3 Hz), 8.11 (d,1H, J=5.1 Hz), 7.87 (d, 1H, J=9.3 Hz), 7.6-7.75 (m, 3H), 7.32 (t, 2H,J=9 Hz), 6.85 (br t, 1H), 6.30 (d, 1H, J=5.1 Hz), 4.25 (br t, 1H), 3.56(br q, 2H), 3.43 (q, 2H, J=6.3 Hz), 1.77 (pent, 2H, J=6.3 Hz). Mass(ES+)=407 (100%).

Example 772-(4-Fluorophenyl)-3-(4-(2-methylthio)pyrimidinyl)-6-trifluoromethylpyrazolo-[1,5-a]pyridine

[0525]

[0526] A solution of2-(4-fluorophenyl)-3-bromo-6-trifluoromethylpyrazolo[1,5-a]pyridine (0.5g, 1.4 mmoles) in dry dioxane (5 mL) was treated with2-methylthio-4-tri(n-butyl)stannylpyrimidine (0.58 g, 1.54 mmoles),silver (II) oxide (0.3 g, 1.54 mmoles) and palladium bis acetonitriledichloride (0.098 mg, 0.14 mmoles). The mixture was heated at 100° C.for 18 h before being allowed to cool to room temperature and filteredthrough celite. Solvent was evaporated under reduced pressure and theresidue purified using silica gel chromatography with 4% ethyl acetatein hexanes to give2-(4-fluorophenyl)-3-(4-(2-methylthio)-pyrimidinyl)-6-trifluoromethylpyrazolo[1,5-a]pyridine(0.23 g, 0.57 mmoles). ¹H NMR (CDCl₃) δ 8.85 (bd, 1H), 8.55 (d, 1H,J=9.5 Hz), 8.30 (d, 1H, J=5.5 Hz), 7.60 (dd, 2H, J=9,5.3 Hz), 7.50(dd,1H, J=10,1.5 Hz), 7.18 (dd, 2H, J=9,9 Hz), 6.72 (d, 1H, J=5.3 Hz), 2.75(s, 3H). MS (+ve electrospray) 405 (100), (MH⁺).

Example 782-(4-Fluorophenyl)-3-(4-(2-methylsulfonyl)pyrimidinyl)-6-trifluoromethylpyrazolo-[1,5-a]pyridine

[0527]

[0528]2-(4-Fluorophenyl)-3-(4-(2-methylthio)-pyrimidinyl)-6-trifluoromethylpyrazolo[1,5-a]pyridine(Example 77. 0.23 g, 0.57 mmoles) was dissolved in methanol (80 mL).Oxone (2.53 g) in water (40 mL) was added. The resulting mixture wasstirred at room temperature for 2 h. Water (400 mL) was added and theresulting fine suspension filtered and washed with water to afford thetitle compound as a white solid (0.246 g, 0.56 mmoles). ¹H NMR (CDCl₃) δ8.88 (bd, 1H), 8.85 (d, 1H. J=9.5 Hz), 8.55 (d, 1H, J=5.5 Hz), 7.65 (dd,1H, J=9,1.5 Hz), 7.58(dd, 2H, J=5, 9 Hz), 7.24 (dd, 2H, J=9, 9 Hz), 7.19(d, 1H, J=5.3 Hz), 3.40 (s, 3H).

Example 792-(4-Fluorophenyl)-3-(4-(2-(3-(4-methylpiperazino)propyl)amino)pyrimidinyl)-6-pyrazolo-[1,5-a]pyridinylcarboxamide

[0529]

[0530] a)N-(3-(4-Methylpiperazino)propyl)-4-[2-(4-fluorophenyl)-6-trifluoromthylpyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

[0531] To a mixture of the enamine described in Example 65f (5.45 g,14.45 mmol) and N-(3-(4-methylpiprazino)propyl)guanidine hydrogensulfate (12.88 g, 3.0 equiv, 43.4 mmol) in anhydrous DMF (50 mL) undernitrogen was added powdered K₂CO₃ (2.75 g, 5.0 equiv, 20.0 mmol). Themixture was stirred and heated at 130° C. for 37 h and then filteredthrough a glass fritted funnel while warm. The solvent was evaporatedunder reduced pressure and the residue was triturated with EtOAc/Hexanes(1:10) to afford a solid that was collected by filtration and driedunder vacuum to give the desired product as an off-white solid, 5.0 g(67%). ¹H NMR (CDCl₃) δ 1.85 (m, 2H), 2.30 (s, 3H), 2.53 (m, 10H), 3.54(m, 2H), 6.00 (br s, 1H), 6.30 (d, 1H), 7.14 (m, 2H), 7.40 (d, 1H), 7.60(m, 2H), 8.08 (d, 1H), 8.49 (d, 1H), 8.81 (s, 1H). MS (ESI⁺) m/z 514.19(M⁺+H).

[0532] b)2-(4-Fluorophenyl)-3-(4-(2-(3-(4-methylpiperazino)propyl)amino)pyrimidinyl)-6-pyrazolo-[1,5-a]pyridinylcarboxamide

[0533]N-(3-(4-Methylpiperazino)propyl)-4-[2-(4-fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine(3.08 g, 1.0 equiv, 5.85 mmol) was added to a solution of sodiummethoxide in methanol, prepared by dissolving sodium metal (2.69 g, 20equiv, 117 mmol) in anhydrous methanol (80 mL). The mixture was stirredand heated at reflux for 8 h and then the reaction was allowed to coolto room temperature. The mixture was concentrated in vacuo tohalf-volume and then water (50 mL) and EtOAc (100 mL) were added. Theorganic phase was separated and the solvent was evaporated to give anorthoester. This orthoester was dissolved in acetone (40 mL) and water(5 mL). p-Toluenesulfonic acid monohydrate (1.64 g, 1.5 equiv, 8.64mmol) was added and the mixture was stirred at 80° C. for about 18 h.The reaction was allowed to cool to room temperature and diluted withEtOAc (300 mL). The resulting solution was washed with brine (100 mL)and saturated sodium bicarbonate (2×100 mL) and then dried over (MgSO₄).The drying agent was removed and the solvent was evaporated to leave anoil that was triturated with EtOAc/Hexanes (1:10) to give a methylester, 3.0 g (99%) as a brown solid. The methyl ester (2.0 g, 1.0 equiv,4.0 mmol) was suspended in methanolic ammonia (10 mL, 2.0 M). Ammoniagas was bubbled through the suspension until the solution was saturated.The flask was sealed and then heated at 105° C. for 17 h (Caution,pressure). The tube was cooled before being opened. The solvents wereevaporated and the solids were triturated with diethyl ether to give thetitle compound as an off-white solid, 1.2 g (60%). ¹H NMR (CD₃OD) δ 1.87(m, 2H), 2.37 (s, 3H), 3.35 (m, 8H), 3.50 (m, 4H), 6.38 (d, 1H), 7.29(m, 2H), 7.67 (m, 2H), 7.88 (d, 1H), 8.08 (d, 1H), 8.47 (d, 1H), 9.22(s, 1H). MS (ESI⁺) m/z 489.23 (M⁺+H).

Example 804-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-[2-(1H-imidazol-5-yl)ethyl]-2-pyrimidinamine

[0534]

[0535] A solution of2-(4-fluorophenyl)-3-(4-(2-methylsulfinyl)pyrimidinyl)pyrazolo[1,5-a]pyridine(Example 58. 0.105 g, 0.31 mmol) and histamine (0.037 g, 0.33 mmol) inxylene (3 mL) was heated at 135° C. for 3 h. The solvent was evaporatedand the residue was purified on silica using methanol/ethyl acetate aseluent to give the title compound as a white solid, 0.044 g (33%).2. ¹HNMR (d₆-DMSO) δ 2.76 (t, J=7.1 Hz, 2H), 3.49 (d, J=6.9 Hz, 2H), 6.17 (d,J=4.4 Hz, 1H), 6.8 (bs, 1H), 7.06 (t, J=6.8 Hz, 1H), 7.17 (bs, 1H), 7.29(t, J=8.8 Hz, 2H), 7.41 (t, J=7.9 Hz, 1H), 7.51 (s, 1H), 7.60 (dd,J=5.6, 8.6 Hz, 2H), 8.03 (d, J=5.1 Hz, 1H), 8.45 (bs, 1H), 8.76 (d,J=6.9 Hz, ₁H), 11.8 (bs, 1H); APESI+MS m/z 400 (M+1)⁻.

Example 814-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-pyridinyl-methyl)-2-pyrimidinamine

[0536]

[0537] In a similar manner as described for Example 60, from2-(4-fluorophenyl)-3-(4-(2-methylsulfinyl)pyrimidinyl)pyrazolo[1,5-a]pyridine(Example 58, 0.083 g, 0.25 mmol) and 3-aminomethylpyridine was obtainedthe title compound as a white solid, 0.071 g (72%). ¹H NMR (CDCl₃) δ4.72 (d, J=6.1 Hz, 2H), 5.59 (bs, 1H), 6.38 (d, J=5.4 Hz, 1H), 6.86 (t,J=6.8 Hz, 1H), 7.12 (t, J=8.7 Hz, 2H), 7.18 (t, J=7.6 Hz, 1H), 7.27 (dd,J=4.9, 7.7 Hz, 1H), 7.58 (dd, J=5.5, 8.4 Hz, 2H), 7.72 (d, J=7.6 Hz,1H), 8.02 (bs, 1H), 8.06 (d, J=5.3 Hz, 1H), 8.45 (d, J=6.8 Hz, 1H), 8.53(d, J=4.6 Hz, 1H), 8.66 (s, 1H); APESI+MS m/z 397 (M+1)⁻.

Example 824-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(2-pyridinylmethyl)-2-pyrimidinamine

[0538]

[0539] In a similar manner as described for Example 60, from2-(4-fluorophenyl)-3-(4-(2-methylsulfinyl)pyrimidinyl)pyrazolo[1,5-a]pyridine(Example 58, 0.085 g, 0.25 mmol) and 2-aminomethylpyridine was obtainedthe title compound as a white solid, 0.047 g (47%). ¹H NMR (CDCl₃) δ4.82 (d, J=5.7 Hz, 2H), 6.13 (bs, 1H), 6.35 (d, J=5.3 Hz, 1H), 6.87 (t,J=6.7 Hz, 1H), 7.12 (t, J=8.6 Hz, 2H), 7.18-7.23 (m, 2H), 7.36 (d, J=7.8Hz, 1H), 7.59 (dd, J=5.5, 8.6 Hz, 2H), 7.65 (dt, J=1.6, 7.7 Hz, 1H),8.07 (d, J=5.3 Hz, 1H), 8.18 (bs, 1H), 8.46 (d, J=7.0 Hz, 1H), 8.60 (d,J=4.9 Hz, 1H); APESI+MS m/z 397 (M+1)⁻.

Example 834-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(4-pyridinyl-methyl)-2-pyrimidinamine

[0540]

[0541] In a similar manner as described for Example 60, from2-(4-fluorophenyl)-3-(4-(2-methylsulfinyl)pyrimidinyl)pyrazolo[1,5-a]pyridine(Example 58) and 4-aminomethylpyridine was obtained the title compoundas a white solid, (80%). ¹H NMR (CDCl₃) δ 4.71 (d, J=6.2 Hz, 2H), 5.69(bs, 1H), 6.38 (d, J=5.3 Hz, 1H), 6.85 (t, J=6.8 Hz, 1H), 7.11 (t, J=8.6Hz, 3H), 7.33 (d, J=5.5 Hz, 2H), 7.58 (dd, J=5.5, 8.6 Hz, 2H), 7.8 (bs,1H), 8.06 (d, J=5.3 Hz, 1H), 8.45 (d, J=6.9 Hz, 1H), 8.58 (d, J=5.9 Hz,2H); APESI+MS m/z 397 (M+1)⁻.

Example 842-(4-Fluorophenyl)-3-(2-phenoxypyrimidin-4-yl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridine

[0542]

[0543] A mixture of2-(4-fluorophenyl)-3-(4-(2-methylsulfonyl)pyrimidinyl)-6-trifluoromethylpyrazolo-[1,5-a]pyridine(Example 78, 0.10 g, 0.23 mmol) phenol (0.10 g, 1.06 mmol) and sodiumcarbonate (0.10 g, 0.94 mmol) in DMF (1 ml) was stirred at 10° C. for 4h. Water was added and the resultant precipitate was collected byfiltration then dried under vacuum to give the title compound as a whitesolid (0.09 g) ¹H NMR (d₆-DMSO) δ 6.78 (d, 1H), 7.29 (m, 2H), 7.35-7.42(m, 3H), 7.48-7.57 (m, 3H), 7.67 (m, 2H), 7.96 (d, 1H), 8.48 (d, 1H),9.50 (brs, 1H), MS (+ve electrospray) 519 (MH+).

Example 853-({4-[2-(4-Fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}oxy)-N,N-dimethylaniline

[0544]

[0545] In a similar manner as described for Example 84 using3-(dimethylamino)phenol, the title compound was obtained as a palepurple solid. ¹H NMR (d₆-DMSO) δ 2.93 (s, 6H), 6.54 (dd, 1H), 6.61 (t,1H), 6.71 (dd, 1H), 6.74 (d, 1H), 7.32 (t, 1H), 7.35-7.45 (m, 3H), 7.67(m, 2H), 8.09 (d, 1H), 8.45 (d, 1H), 9.50 (brs, 1H). MS (+veelectrospray) 494 (MH+).

Example 863-[2-(2,5-Dimethylphenoxy)pyrimidin-4-yl]-2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridine

[0546]

[0547] In a similar manner as described for Example 84 using2,5-dimethylphenol, the title compound was obtained as an off-whitesolid. ¹H NMR (d₆-DMSO) δ 2.08 (s, 3H), 2.34 (s, 3H), 6.75 (d, 1H), 7.05(d, 1H), 7.12 (dd, 1H), 7.30 (d, 1H), 7.35-7.48 (m, 3H), 7.66 (m, 2H),7.86 (d, 1H), 8.45 (d, 1H), 9.50 (brs, 1H). MS (+ve electrospray) 479(MH+).

Example 87N-[3-(dimethylamino)propyl]-N-[4-(2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl]amine

[0548]

[0549] a) 1-(4-Fluorophenyl)-2-(2-(5-trifluoromethyl)pyridyl)ethanone.

[0550] To a solution of 4-fluoroacetophenone (13.8 g, 0.100 mol) and2-chloro-5-trifluoromethylpyridine (20.0 g, 0.110 mol) intetrahydrofuran (400 mL) was added sodium hydride (95%, 5.56 g, 0.220mol) in several portions. The reaction was stirred at room temperaturefor 72 h then carefully quenched by the addition of water (300 mL) anddiethyl ether (200 mL). The organic layer was separated and extractedwith 6N HCl (2×300 mL). The aqueous extracts were cooled to 0° C. and 6NNaOH was used to adjust the solution to pH 12. The mixture was thenextracted with diethyl ether and the combined organic extracts weredried (MgSO₄). The drying agent was removed by filtration and thefiltrate was evaporated to dryness to afford the title compound as atautomeric mixture, 20.9 g (73%). ¹H NMR (CDCl₃) δ 8.87 (s), 8.63(s),8.14 (dd, J=5.1, 8.4 Hz), 8.007.83(m), 7.51 (d, J=8.4 Hz), 7.22-7.12(m), 6,13 (s), 4.60 (s). MS (ES+ve): 284 (100, M⁺+1).

[0551] b) 1-(4-Fluorophenyl)-2-(2-(5-trifluoromethyl)pyridyl)ethanoneOxime.

[0552] To a solution of1-(4-fluorophenyl)-2-(2-(5-trifluoromethyl)pyridyl)ethanone (80.0 g,0.282 mol) in methanol (1 L) at room temperature was added 10% aqueoussodium hydroxide (436 mL, 1.09 mol). The resulting solution was stirredvigorously as solid hydroxylamine hydrochloride (98.0 g, 1.40 mol) wasadded. The mixture was heated to reflux for 2 h, treated withdecolorizing charcoal while hot, then filtered through Celite while hot.The filtrate was concentrated to one-half its original volume and thencooled to 0° C. with stirring for one hour. The resulting solids werecollected by filtration, washed with water, and dried under vacuum at50° C. overnight to provide the title compound as a light yellow powder,73.9 g (88%). ¹H NMR (d₆-DMSO) δ 11.60(s, 1H), 8.86(s, 1H), 8.14(dd, 1H,J=2.1, 8.1 Hz), 7.78(dd, 2H, J=5.7, 9.0 Hz), 7.53(d, 1H, J=8.4 Hz),7.23(t, 2H, J=9.0 Hz), 4.40(s, 2H). MS (ES+ve): 299 (70, M⁺+1).

[0553] c)3-(4-Fluorophenyl)-2-(2-(5-trifluoromethyl)pyridyl)-2H-azirine.

[0554] To a solution of1-(4-fluorophenyl)-2-(2-(5-trifluoromethyl)pyridyl)ethanone oxime (25.0g, 0.084 mol) in methylene chloride (400 mL) was added triethylamine(46.7 mL, 0.335 mol). The solution was cooled to 0° C. under a nitrogenatmosphere, and trifluoroacetic anhydride (140.1 mL, 0.100 mol) wasadded dropwise. The reaction was stirred for 0.5 h then quenched withwater. The organic layer was separated and dried (MgSO₄). The dryingagent was removed by filtration and the solvent was evaporated from thefiltrate to leave an oil. The residue was loaded onto a silica gelcolumn and eluted with 15% ethyl acetate in hexanes to give the titlecompound as an oil which solidified on standing, 19.4 g (82%). ¹H NMR(CDCl₃) δ 8.76(s, 1H), 7.93(dd, 2H, J=5.4, 8.7 Hz), 7.83(dd, 1H, J=2.1,8.4 Hz), 7.27(t, 2H, J=8.7 Hz), 7.21(d, 1H, J=8.1 Hz), 3.54 (s, 1H). MS(ES+ve): 281 (100, M⁺+1).

[0555] d) 2-(4-Fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridine.

[0556] 3-(4-Fluorophenyl)-2-(2-(5-trifluoromethyl)pyridyl)-2H-azirine(40.0 g, 0.143 mol) was dissolved in 1,2,4-trichlorobenzene (400 mL) andthe mixture was heated to 200° C. for 10 h. The reaction mixture wasthen cooled to room temperature and poured onto a silica gel column. Thecolumn was eluted with hexanes to remove the 1,2,4-trichlorobenzene, andthen with 20% diethyl ether in hexanes to elute the product. The desiredfractions were combined and the solvent was evaporated under reducedpressure to leave the title compound, 28.7 g (71%). ¹H NMR (CDCl₃) δ8.84(s, 1H), 7.98(dd, 2H, J=5.4, 8.7 Hz), 7.65(d, 1H, J=9.3 Hz), 7.28(d,1H, J=9.3 Hz), 7.20(t, 2H, J=8.7 Hz), 6.88(s, 1H). MS (ES+ve): 281 (100,M⁺+1).

[0557] e)2-(4-Fluorophenyl)-3-acetyl-6-trifluoromethylpyrazolo[1,5-a]pyridine.

[0558] To a mixture of2-(4-fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridine (10.30 g,36.76 mmol) and acetic anhydride (100 mL) was added conc. sulfuric acid(10 drops) and the mixture was stirred and heated at reflux for 1 h. Thereaction mixture was cooled to room temperature and poured into icewater (300 mL). 2N Aqueous sodium hydroxide solution was added to raisethe pH of the solution to about 10 and the resulting orange precipitatewas collected by filtration. The solid was washed with water, air-dried,and then dried under vacuum to afford the title compound as an orangesolid, 11.87 g (quant.). ¹H NMR (d₆-DMSO) δ 9.58 (s, 1H), 8.41 (d, 1H,J=9.3 Hz), 7.89 (d, 1H, J=9.5 Hz), 7.74 (m, 2H), 7.39 (m, 2H), 2.22 (s,3H). MS (+ve ion electrospray) 323 (70), (MH+).

[0559] f)2-(4-fluorophenyl)-3-(3-(dimethylamino)-2-propenoyl)-6-trifluoromethylpyrazolo[1,5-a]pyridine.

[0560] A mixture of2-(4-fluorophenyl)-3-acetyl-6-trifluoromethylpyrazolo[1,5-a]pyridine(11.85 g), 36.77 mmol) and N,N-dimethylformamide dimethyl acetal (100mL) was stirred at reflux for 17 h. The mixture was cooled to roomtemperature and then to 0° C. The resulting orange precipitate wascollected by filtration, washed with cold hexanes, and dried undervacuum to afford the title compound as an orange solid, 10.17 g (73%).¹H NMR (d₆-DMSO) δ 9.44 (s, 1H), 8.22 (d, 1H, J=9.4 Hz), 7.75 (m, 2H),7.65 (d, 1H, J=9.5 Hz), 7.56 (d, 1H, J=12.4 Hz), 7.35 (m, 2H), 5.05 (d,1H, J=12.3 Hz), 3.04 (s, 3H), 2.56 (s, 3H). MS (+ve ion electrospray)377 (80), (M+).

[0561] g)N-[3-(dimethylamino)propyl]-N-[42-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl}pyrimidin-2-yl]amine.

[0562] To a mixture of2-(4-fluorophenyl)-3-(3-(dimethylamino)-2-propenoyl)-6-trifluoromethylpyrazolo[1,5-a]pyridine(2.52 g, 6.68 mmol) and N-(3-dimethylaminopropyl)guanidine (3.23 g, 2.0equiv, 13.4 mmol) in anhydrous tetrahydrofuran (50 mL) under nitrogenwas added a solution of potassium t-butoxide in t-butanol (26.7 mL, 4.0equiv, 26.7 mmol). The mixture was stirred and heated at reflux forabout 17 h and then was allowed to cool to room temperature. Water (50mL) and diethyl ether (100 mL) were added and the organic phase wasseperated. The aqueous phase was extracted with 25%tetrahydrofuran/ether. The combined organic phases were dried overanhydrous sodium sulfate and activated carbon. The drying agents wereremoved by filtration and the filtrate was concentrated to give thetitle compound as a light yellow solid 2.9 g, (95%). ¹H NMR (CDCl₃) δ1.89 (m, 2H), 2.37, (s, 6H), 2.58 (br, 2H), 3.55 (dd, 2H, J=6.4, 12.4Hz), 5.87 (br, 1H), 6.30 (d, 1H, J=5.2 Hz), 7.12 (t, 2H, J=8.4 Hz), 7.40(d, 1H, J=9.2 Hz), 7.58 (dd, 2H, J=5.6, 8.8 Hz), 8.06 (d, 1H, J=5.2 Hz),8.46 (d, 1H, J=9.6 Hz), 8.79 (s, 1H). MS (ES+) m/z 459.50 (M⁺+H), 414.50(M⁺−44).

Example 88N-[3-(dimethylamino)propyl-N-[4-{6-(trifluoromethyl)-2-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyridin-3-yl}pyrimidin-2-yl]amine

[0563]

[0564] a)3-Bromo-6-(trifluoromethyl)-2-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyridine.

[0565] In an analogous procedure to Example 91 (a),2-(4-trifluoromethylphenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridinewas converted to the title compound;

[0566]¹H NMR (d₆-DMSO) δ 9.47 (1H, s), 8.21 (2H, d), 7.94 (2H, d), 7.83(1H, d), 7.62 (1H, d).

[0567] b) Methyl4-{6-(trifluoromethyl)-2-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyridin-3-yl}pyrimidin-2-ylsulfide

[0568] A mixture of3-bromo-6-(trifluoromethyl)-2-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyridine(0.82 g), 2-(methylthio)-4-(tributylstannyl)pyrimidine (0.83 g),dichlorobis(triphenylphosphine)palladium (0.14 g) and silver (I) oxide(0.43 g) in 1,4-dioxane (10 mL) was heated to reflux for 18 h. Themixture was cooled, filtered and the filtrate concentrated to dryness.The residue was purified by chromatography eluting with an increasinggradient from cyclohexane to cyclohexane-diethylether (94:6) to give,after concentration to dryness of the appropriate fractions, the titlecompound as a cream solid (0.46 g); ¹H NMR (d₆-DMSO) δ 9.58 (1H, s),8.50 (1H, d), 8.46 (1H, d), 7.90 (2H, d), 7.84 (2H, d), 7.82 (1H, dd),6.94 (1H, d), 2.43 (3H, s); m/z 455 (M+1)⁺.

[0569] c) Methyl4-{6-(trifluoromethyl)-2-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyridin-3-yl}pyrimidin-2-ylsulfone.

[0570] Oxone (6.93 g) in water (115 mL) was mixed with methyl4-{6-(trifluoromethyl)-2-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyridin-3-yl}pyrimidin-2-ylsulfide (0.66 g) in methanol (230 mL) and stirred for 2 h. It wasdiluted with water (1L) and the resultant suspension removed byfiltration and dried at reduced pressure to give the title compound as abeige solid (0.63 g); ¹H NMR (CDCl₃) δ 8.90 (1 HS), 8.86 (1H, d), 8.59(1H, d), 7.82 (2H, d), 7.76 (2H, d), 7.67 (1H, dd), 7.16 (1H, d), 3.39(3H, s); m/z 487 (M+1)⁺.

[0571] d)N-[3-(dimethylamino)propyl]-N-[4-{6-(trifluoromethyl)-2-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyridin-3-yl}pyrimidin-2-yl]amine.

[0572] 3-(Dimethylamino)propylamine (0.04 mL) and methyl4-{6-(trifluoromethyl)-2-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyridin-3-yl}pyrimidin-2-ylsulfone (0.02 g) were mixed at room temperature and heated with anairgun until a homogenous melt was obtained (2 min). Upon cooling, waterwas added. The precipitated solid was filtered and dried to give thetitle compound as a white solid (0.012 g); ¹H NMR (d₆-DMSO) δ 9.52 (1H,s), 8.50 (1H, bs), 8.16 (1H, d), 7.87 (4H, dd), 7.69 (1H, d), 7.26 (1H,bs), 6.34 (1H, bs), 3.25 (2H, bs), 2.24 (2H, bs), 2.11 (6H, s), 1.63(2H, bs); m/z 509 (M+1)+.

Example 89N-[4-{2-[3-chloro-4-fluorophenyl]-6-(trifluoromethyl)pyrazolo-[1,5-a]pyridin-3-yl}pyrimidin-2-yl]-N-[3-(dimethylamino)propyl]amine

[0573]

[0574] a)3-Bromo-2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridine.

[0575] In an analogous procedure to Example 91(a),2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridinewas converted to the title compound;

[0576]¹H NMR (CDCl₃) δ 8.77 (1H, s), 8.14 (1H, dd), 7.97 (1H, m), 7.65(1H, d), 7.37 (1H, dd), 7.27 (1H, dd).

[0577] b)4-[2-(3-Chloro-4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-ylmethyl Sulfide.

[0578] A mixture of3-bromo-6-(trifluoromethyl)-2-(3-chloro-4-fluorophenyl)pyrazolo[1,5-a]pyridine(0.79 g), 2-(methylthio)-4-(tributylstannyl)pyrimidine (0.83 g),dichlorobis(triphenylphosphine)palladium (0.14 g) and silver (I) oxide(0.43 g) in 1,4-dioxane (10 mL) was heated to reflux for 18 h. Themixture was cooled, filtered and the filtrate concentrated to dryness.The residue was purified by chromatography eluting with an increasinggradient from cyclohexane to cyclohexane-diethylether (94:6) to give,after concentration to dryness of the appropriate fractions, the titlecompound as a cream solid (0.54 g); ¹H NMR (CDCl₃) δ 8.84 (1H, s), 8.52(1H, d), 8.34 (1H, d), 7.72 (1H, dd), 7.51 (1H, dd), 7.47 (1H, m), 7.25(1H, dd), 6.74 (1H, d), 2.61 (3H, s).

[0579] c)4-[2-(3-Chloro-4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-ylmethyl Sulfone.

[0580] Oxone (5.90 g) in water (100 mL) was mixed with4-[2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-ylmethyl sulfide (0.54 g) in methanol (200 mL) and stirred for 2 h. Themethanol was removed at reduced pressure and the mixture diluted withwater (100 mL). The resultant suspension was removed by filtration anddried at reduced pressure to give the title compound as a yellow solid(0.52 g); ¹H NMR (CDCl₃) δ 8.87 (1H, s), 8.83 (1H, d), 8.61 (1H, d),7.71 (1H, dd), 7.66 (1H, dd), 7.48 (1H, m), 7.32 (1H, dd), 7.21 (1H, d),3.40 (3H, s).

[0581] d)N-[4-{2-[3-chloro-4-fluorophenyl]-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl]-N-[3-(dimethylaminolpropyl]amine.

[0582] In an analogous procedure to Example 88d),4-[2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-ylmethyl sulfone (0.02 g) and 3-(dimethylamino)propylamine (0.04 mL) gavethe title compound; ¹H NMR (d₆-DMSO) δ 9.50 (1H, s), 8.53 (1H, bs), 8.18(1H, d), 7.84 (1H, dd), 7.70 (1H, d), 7.63 (1H, m), 7.57 (1H, dd), 7.28(1H, bs), 6.40 (1H, bs), 3.29 (2H, bs), 2.25 (2H, bm), 1.65 (6H, bs);m/z 493 (M+1)⁺.

Example 90N-{4-[2-(3-chlorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-[3-(dimethylamino)propyl]amine

[0583]

[0584] a)3-Bromo-2-(3-chlorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridine.

[0585] In an analogous procedure to Example 91 (a),2-(3-chlorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridine wasconverted to the title compound;

[0586]¹H NMR (CDCl₃) δ 8.79 (1H, s), 8.06 (1H, s), 7.97 (1H, m), 7.66(1H, d), 7.45 (2H, d), 7.36 (1H, d).

[0587] b) Methyl4-{6-(trifluoromethyl)-2-[3-chlorophenyl]pyrazolo[1,5-a]pyridin-3-yl}pyrimidin-2-ylsulfide.

[0588] A mixture of3-bromo-6-(trifluoromethyl)-2-[3-chlorophenyl]pyrazolo[1,5-a]pyridine(2.0 g), 2-(methylthio)-4-(tributylstannyl)pyrimidine (2.32 g),dichlorobis(triphenylphosphine)palladium (0.37 g) and silver (I) oxide(1.23 g) in 1,4-dioxane (20 mL) was heated to reflux for 20 h. Themixture was cooled, filtered and the filtrate concentrated to dryness.The residue was purified by chromatography eluting withcyclohexane-ethylacetate (90:10) to give, after concentration to drynessof the appropriate fractions, the title compound as a cream solid (0.95g); ¹H NMR (d₆-DMSO) δ 9.58 (1H, s), 8.53-8.47 (2H, m), 7.84 (1H, d),7.70 (1H, s), 7.63 (1H, m), 7.57 (2H, m), 6.94 (1H, d) 2.43 (3H, s); m/z421 (M+1)⁺.

[0589] c) Methyl4-{6-(trifluoromethyl)-2-[3-chlorophenyl]pyrazolo[1,5-a]pyridin-3-yl}pyrimidin-2-ylsulfone.

[0590] Oxone (9.5 g) in water (75 mL) was mixed with methyl4-{6-(trifluoromethyl)-2-[3-chlorophenyl]pyrazolo[1,5-a]pyridin-3-yl}pyrimidin-2-ylsulfide (0.95 g) in methanol (200 mL) and stirred for 2 h. The methanolwas removed under reduced pressure and then water added (200 ml). Theresultant suspension was removed by filtration and dried at reducedpressure to give the title compound as a pink solid (0.80 g); ¹H NMR(d₆-DMSO) δ 9.67 (1H, s), 8.90 (1H, d), 8.64 (1H, d), 7.98 (1H, dd),7.77 (1H, s), 7.71-7.56 (3H, m), 7.44 (1H, d), 3.42 (3H, s); m/z453(M+1)⁺.

[0591] d)N-{4-[2-(3-chlorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-[3-(dimethylamino)propyl]amine.

[0592] In an analogous procedure to Example 88(d),4-[2-(3-chlorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-ylmethyl sulfone (0.02 g) and 3-(dimethylamino)propylamine (0.04 mL) gavethe title compound; ¹H NMR (d₆-DMSO) δ 9.51 (1H, s), 8.49 (1H, bs), 8.16(1H, d), 7.72-7.65 (2H, m), 7.61-7.51 (3H, m), 7.28 (1H, bs), 6.32 (1H,bs), 3.30 (2H, bs), 2.25 (2H, t), 2.12 (6H, s), 1.66 (2H, m); m/z475(M+1)⁺.

Example 91N-(4-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-[2-(dimethylamino)ethyl]amine

[0593]

[0594] a)3-Bromo-2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridine.

[0595] 2-(4-Fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridine (5g, Example 1(d)) in tetrahydrofuran (50 mL) was treated withN-bromosuccinimide (3.5 g). After 1 h, the mixture was concentrated invacuo and partitioned between dichloromethane and 2N NaOH. The organicextract was dried and concentrated. The residue was purified bychromatography on silica to give the title compound (5.2 g); ¹H NMR(CDCl₃) δ 8.78 (1H, s), 8.05 (2H, dd), 7.65 (1H, d), 7.35 (1H, dd), 7.20(2H, dd); m/z 359(M+1)+.

[0596] b)4-[2-(4-Fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-ylMethyl Sulfide.

[0597] A mixture of3-bromo-6-(trifluoromethyl)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine(0.50 g), 2-(methylthio)-4-(tributylstannyl)pyrimidine (0.58 g),dichlorobis(triphenylphosphine)palladium (0.098 g) and silver (I) oxide(0.30 g) in 1,4-dioxane.(5 mL) was heated to reflux for 18 h. Themixture was cooled, filtered and the filtrate concentrated to dryness.The residue was purified by chromatography eluting withcyclohexane-ethylacetate (96:4) to give, after concentration to drynessof the appropriate fractions, the title compound as a cream solid (0.23g); ¹H NMR (CDCl₃) δ 8.85 (1H, bd), 8.55 (1H, d), 8.30 (1H, d), 7.60(2H, dd), 7.50 (1H, dd), 7.18 (2H, dd), 6.72 (1H, d), 2.75 (3H, s); m/z405 (M+1)⁺.

[0598] c)4-[2-(4-Fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-ylMethyl Sulfone.

[0599] Oxone (2.53 g) in water (40 mL) was mixed with4-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-ylmethyl sulfide (0.23 g) in methanol (80 mL) and stirred for 2 h. Themethanol was removed at reduced pressure and the mixture diluted withwater (400 mL). The resultant suspension was removed by filtration anddried at reduced pressure to give the title compound as a yellow solid(0.25 g); ¹H NMR (CDCl₃) δ 8.88 (1H, s), 8.85 (1H, d), 8.55 (1H, d),7.65 (1H, dd), 7.58 (2H, dd), 7.24 (2H, dd), 7.19 (1H, d), 3.40 (3H, s).

[0600] d)N-{4-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-[2-(dimethylamino)ethyl]amine.

[0601] In an analogous procedure to Example 88(d),4-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-ylmethyl sulfone (0.02 g) and 2-(dimethylamino)ethylamine (0.04 mL) gavethe title compound; ¹H NMR (CDCl₃) δ 8.83 (1H, s), 8.51 (1H, d), 8.11(1H, d), 7.63 (2H, dd), 7.43 (1H, dd), 7.15 (2H, dd), 6.33 (1H, d), 5.75(1H, bs), 3.60 (2H, dt), 2.65 (2H, bt), 2.35 (6H, s); m/z 445 (M+1)+.

Example 92N-[4-(diethylamino)butyl]-N-(4-{6-(trifluoromethyl)-2-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyridin-3-yl}pyrimidin-2-yl)amine

[0602]

[0603] In an analogous procedure to Example 88(d), methyl4-{6-(trifluoromethyl)-2-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyridin-3-yl}pyrimidin-2-ylsulfone (0.02 g) and 4-(diethylamino)butylamine (0.04 mL) gave the titlecompound; ¹H NMR (d₆-DMSO) δ 9.48 (1H, s), 8.44 (1H, bs), 8.14 (1H, d),7.83 (4H, dd), 7.65 (1H, d), 6.96 (1H, bs), 6.36 (1H, bs), 2.36 (2H,bs), 2.28 (4H, bs), 1.44 (4H, bt), 1.33 (2H, bd); m/z 450, 535.

Example 93N-{4-[2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyrazolo-[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-[4-(diethylamino)butyl]amine

[0604]

[0605] In an analogous procedure to Example 88(d),4-[2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-ylmethyl sulfone (0.02 g) and 4-(diethylamino)butylamine (0.04 mL) gavethe title compound; ¹H NMR (d₆-DMSO) δ 9.51 (1H, s), 8.49 (1H, bs), 8.19(1H, d), 7.85 (1H, dd), 7.71 (1H, d), 7.64 (1H, m), 7.58 (1H, dd), 7.31(1H, bs), 6.40 (1H, bs), 3.26 (2H, bs), 2.43 (4H, q), 2.36 (2H, bm),1.53 (2H, bs), 1.43 (2H, bs), 0.93 (6H, t); m/z 535 (M+1)+.

Example 94N-{4-[2-(3-chlorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-[4-(diethylamino)butyl]amine

[0606]

[0607] In an analogous procedure to Example 88(d),4-[2-(3-chlorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-ylmethyl sulfone (0.02 g) and 4-(diethylamino)butylamine (0.04 mL) gavethe title compound; ¹H NMR (d₆DMSO) δ 9.51 (1H, s), 8.47 (1H, bs), 8.14(1H, d), 7.73-7.66 (2H, m), 7.6-17.51 (3H, m), 7.31 (1H, bs), 6.32 (1H,bs), 3.27 (2H, bs), 2.41 (4H, q), 2.35 (2H, t), 1.53 (2H, m), 1.43 (2H,m), 0.91 (6H, t); m/z 517(M+1)⁺.

Example 95N-[2-(diethylamino)ethyl]-N-(4(6-(trifluoromethyl)-2-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyridin-3-yl}pyrimidin-2-yl)amine

[0608]

[0609] In an analogous procedure to Example 88(d), methyl4-{6-(trifluoromethyl)-2-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyridin-3-yl}pyrimidin-2-ylsulfone (0.02 g) and 2-(diethylamino)ethylamine (0.04 mL) gave the titlecompound; ¹H NMR (d₆-DMSO) δ 9.53 (1H, s), 8.48 (1H, bs), 8.19 (1H, d),7.87 (4H, dd), 7.70 (1H, d), 6.99 (1H, bs), 6.38 (1H, bs), 0.93 (6H,bt); m/z 450, 523 (M+1)⁺.

Example 96N-{4-[2-(3-chlorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-[2-(diethylamino)ethyl]amine

[0610]

[0611] In an analogous procedure to Example 88(d),4-[2-(3-chlorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-ylmethyl sulfone (0.02 g) and 2-(diethylamino)ethylamine (0.04 mL) gavethe title compound; ¹H NMR (d₆-DMSO) δ 9.51 (1H, s), 8.47 (1H, bs), 8.16(1H, d), 7.72-7.65 (2H, m), 7.61-7.51 (3H, m), 7.00 (1H, bs), 6.34 (1H,bs), 0.93 (6H, bs); m/z 489(M+1)⁺.

Example 97N-[2-(dipropylamino)ethyl]-N-(4-{6-(trifluoromethyl)-2-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyridin-3-yl}pyrimidin-2-yl)amine

[0612]

[0613] In an analogous procedure to Example 88(d), methyl4-{6-(trifluoromethyl)-2-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyridin-3-yl}pyrimidin-2-ylsulfone (0.02 g) and 2-(dipropylamino)ethylamine (0.04 mL) gave thetitle compound; ¹H NMR (d₆-DMSO) δ 9.52 (1H, s), 8.46 (1H, bs), 8.18(1H, d), 7.87 (4H, dd), 7.68 (1H, d), 6.96 (1H, bs), 6.37 (1H, bs), 2.33(4H, bs), 1.37 (4H, bs), 1.48 (4H, bs), 0.79 (6H, bs); m/z 450, 551(M+1)⁺.

Example 98N-{4-[2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyrazolo-[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-[2-(dipropylamino)ethyl]amine

[0614]

[0615] In an analogous procedure to Example 88(d),4-[2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-ylmethyl sulfone (0.02 g) and 2-(dipropylamino)ethylamine (0.04 mL) gavethe title compound; ¹H NMR (d₆-DMSO) δ 9.50 (1H, s), 8.45 (1H, bs), 8.19(1H, d), 7.84 (1H, dd), 7.68 (1H, d), 7.63 (1H, m), 7.56 (1H, dd), 6.97(1H, bs), 6.41 (1H, bs), 2.34 (4H, bs), 1.37 (4H, bs), 0.80 (6H, bs);m/z 535 (M+1)⁺.

Example 99N-{4-[2-(3-chlorophenyl)-6-(trifluororbethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-[2-(dipropylamino)ethyl]amine

[0616]

[0617] In an analogous procedure to Example 88(d),4-[2-(3-chlorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-ylmethyl sulfone (0.02 g) and 2-(dipropylamino)ethylamine (0.04 mL) gavethe title compound; ¹H NMR (d₆-DMSO) δ 9.51 (1H, s) 8.47 (1H, bs), 8.16(1H, d), 7.66 (2H, m), 7.61-7.51 (3H, m), 6.97 (1H, bs), 6.34 (1H, bs),2.35 (4H, bs), 1.37 (4H, m), 0.80 (6H, s); m/z 517(M+1)⁺.

Example 100N-{4-[2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyrazolo-[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-[2-(diisopropylamino)ethyl]amine

[0618]

[0619] In an analogous procedure to Example 88(d),4-[2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-ylmethyl sulfone (0.02 g) and 2-(diisopropylamino)ethylamine (0.04 mL)gave the title compound; ¹H NMR (d₆-DMSO) δ 9.51 (1H, s), 8.40 (1H, bs),8.21 (1H, d), 7.84 (1H, dd), 7.68 (1H, d), 7.64 (1H, m), 7.57 (1H, dd),7.03 (1H, bs), 6.47 (1H, bs), 3.23 (2H, bs), 2.94 (2H, bs), 0.95(12H,bs); m/z 535 (M+1)⁺.

Example 101N-{4-[2-(3-chlorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl)-N-[2-(diisopropylamino)ethyl]amine

[0620]

[0621] In an analogous procedure to Example 88(d),4-[2-(3-chlorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-ylmethyl sulfone (0.02 g) and 2-(diisopropylamino)ethylamine (0.04 mL)gave the title compound; ¹H NMR (d₆-DMSO) δ 9.50 (1H, s), 8.40 (1H, bs),8.16 (1H, d), 7.71-7.63 (2H, m), 7.61-7.51 (3H, m), 7.00 (1H, bs), 6.34(1H, bs), 3.24 (2H, bs), 2.93 (2H, m), 0.95(12H, d); m/z 517(M+1)⁺.

Example 102N-{4-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-(2-pyrrolidin-1-ylethyl)amine

[0622]

[0623] 2-Pyrrolidin-1-ylethylamine (0.04 mL) and4-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-ylmethyl sulfone (0.02 g) were mixed at room temperature and heated withan airgun until a homogenous melt was obtained (2 min). Upon cooling,water was added. The precipitated solid was filtered and dried to givethe title compound as a beige solid (0.012 g); ¹H NMR (CDCl₃) δ 8.83(1H, s), 8.51 (1H, d), 8.11 (1H, d), 7.63 (2H, dd), 7.43 (1H, dd), 7.15(2H, dd), 6.33 (1H, d), 5.75 (1H, bs), 3.58 (2H, dt), 2.76 (2H, t), 2.58(2H, bt), 1.81 (2H, bm); m/z 471 (M+1)⁺.

Example 103N-(2-pyrrolidin-1-ylethyl)-N-(4-{6-(trifluoromethyl)-2-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyridin-3-yl}pyrimidin-2-yl)amine

[0624]

[0625] In an analogous procedure to Example 102, methyl4-{6-(trifluoromethyl)-2-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyridin-3-yl}pyrimidin-2-ylsulfone (0.02 g), 2-pyrrolidin-1-ylethylamine (0.04 mL) gave the titlecompound; ¹H NMR (d₆-DMSO) δ 9.53 (1H, s), 8.50 (1H, bs), 8.19 (1H, d),7.88 (4H, dd), 7.70 (1H, d), 7.10 (1H, bs), 6.39 (1H, bs), 2.44 (4H,bs), 1.68 (4H, bs); m/z 521 (M+1)⁺.

Example 104N-{4-[2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyrazolo-[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-(2-pyrrolidin-1-ylethyl)amine

[0626]

[0627] 2-Pyrrolidin-1-ylethylamine (0.04 mL) and4-[2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-ylmethyl sulfone (0.02 g) were mixed at room temperature and heated withan airgun until a homogenous melt was obtained (2 min). Upon cooling,water was added. The precipitated solid was filtered and dried to givethe title compound as a beige solid (0.012 g); ¹H NMR (d₆-DMSO) δ 9.50(1H, s), 8.48 (1H, bs), 8.18 (1H, d), 7.83 (1H, d), 7.68 (1H, dd), 7.62(1H, m), 7.56 (1H, dd), 7.12 (1H, bs), 6.42 (1H, bs), 2.44 (2H, bs),1.67 (4H, bs); m/z 505 (M+1)⁺.

Example 105N-{4-[2-(3-chlorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-(2-pyrrolidin-1-ylethyl)amine

[0628]

[0629] In an analogous procedure to Example 104,4-[2-(3-chlorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-ylmethyl sulfone (0.02 g) and 2-pyrrolidin-1-ylethylamine (0.04 mL) gavethe title compound; ¹H NMR (d₆-DMSO) δ 9.51 (1H, s), 8.49 (1H, bs), 8.17(1H, d), 7.72-7.65 (2H, m), 7.61-7.51 (3H, m), 7.13 (1H, bs), 6.37 (1H,bs), 2.57 (2H, bs), 2.45 (4H, bs), 1.68 (4H, s); m/z 487(M+1)⁺.

Example 106N-{4-[2-(3-chlorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-(4-pyrrolidin-1-ylbutyl)amine

[0630]

[0631] In an analogous procedure to Example 104,4-[2-(3-chlorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-ylmethyl sulfone (0.02 g) and 4-pyrrolidin-1-ylbutylamine (0.04 mL) gavethe title compound; ¹H NMR (d₆-DMSO) δ 9.51 (1H, s), 8.47 (1H, bs), 8.16(1H, d), 7.72-7.65 (2H, m), 7.61-7.51 (3H, m), 7.31 (1H, bs), 6.32 (1H,bs), 3.27 (2H, bs), 2.37 (6H, bs), 1.64 (4H, bs), 1.55 (2H, m), 1.48(2H, m); m/z. 515(M+1)⁺.

Example 107N-(4-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-(2-piperidin-1-ylethyl)amine

[0632]

[0633] In an analogous procedure to Example 104,4-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-ylmethyl sulfone (0.02 g), 2-piperidin-1-ylethylamine (0.04 mL) gave thetitle compound; ¹H NMR (CDCl₃) δ 8.83 (1H, s), 8.51 (1H, d), 8.11 (1H,d), 7.63 (2H, dd), 7.43 (1H, dd), 7.15 (2H, dd), 6.33 (1H, d), 5.75 (1H,bs), 3.60 (2H, dt), 2.55 (2H, t), 2.50 (4H, bm), 1.60-1.50 (6H, m); m/z485 (M+1)+.

Example 108N-(2-piperidin-1-ylethyl)-N-(4-{6-(trifluoromethyl)-2-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyridin-3-yl}pyrimidin-2-yl)amine

[0634]

[0635] In an analogous procedure to Example 104, methyl4-{6-(trifluoromethyl)-2-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyridin-3-yl}pyrimidin-2-ylsulfone (0.02 g), 2-piperidin-1-ylethylamine (0.04 mL) gave the titlecompound; ¹H NMR (d₆-DMSO) δ 9.52 (1H, s), 8.47 (1H, bs), 8.19 (1H, d),7.87 (4H, dd), 7.69 (1H, d), 7.02 (1H, bs), 6.41 (1H, bs), 2.46-2.24(4H, bm), 1.48 (4H, bt), 1.37 (2H, bs); m/z 450, 535 (M+1)+.

Example 109N-{4-[2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-(2-pipridin-1-ylethyl)amin

[0636]

[0637] In an analogous procedure to Example 104,4-[2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-ylmethyl sulfone (0.029), 2-piperidin-1-ylethylamine (0.04 mL) gave thetitle compound; ¹H NMR (d₆-DMSO) δ 9.52 (1H, s), 8.47 (1H, bs), 8.20(1H, d), 7.84 (1H, dd), 7.69 (1H, d), 7.63 (1H, m), 7.57 (1H, dd), 7.04(1H, bs), 6.45 (1H, bs), 2.41 (2H, bs), 2.33 (4H, bm), 1.49 (4H, bm),1.38 (2H, bm); m/z 519 (M+1)⁺.

Example 110N-{4-[2-(3-chlorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-(2-piperidin-1-ylethyl)amine

[0638]

[0639] In an analogous procedure to Example 104,4-[2-(3-chlorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-ylmethyl sulfone (0.02 g) and 2-piperidin-1-ylethylamine (0.04 mL) gavethe title compound; ¹H NMR (d₆-DMSO) δ 9.51 (1H, s), 8.49 (1H, bs), 8.16(1H, d), 7.70-7.65 (2H, m), 7.61-7.51 (3H, m), 7.03 (1H, bs), 6.37 (1H,bs), 2.42 (2H, m), 2.33 (4H, m), 1.49 (4H, m), 1.38 (2H, m); m/z 501(M+1)⁺.

Example 111N-{4-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-(2-piperidin-1-ylpropyl)amine

[0640]

[0641] In an analogous procedure to Example 104,4-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-ylmethyl sulfone (0.02 g), 2-piperidin-1-ylpropylamine (0.04 mL) gave thetitle compound; ¹H NMR (CDCl₃) δ 8.83 (1H, s), 8.51 (1H, d), 8.11 (1H,d), 7.63 (2H, dd), 7.43 (1H, dd), 7.15 (2H, dd), 6.33 (1H, d), 5.75 (1H,bs), 3.55 (2H, dt), 2.50 (2H, t), 2.45 (4H, m), 1.85 (2H, m), 1.57 (4H,m), 1.50 (2H, m); m/z 499 (M+1)⁺.

Example 112N-(3-piperidin-1-ylpropyl)-N-(4-{6-(trifluoromethyl)-2-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyridin-3-yl}pyrimidin-2-yl)amine

[0642]

[0643] In an analogous procedure to Example 104, methyl4-{6-(trifluoromethyl)-2-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyridin-3-yl}pyrimidin-2-ylsulfone (0.02 g), 3-piperidin-1-ylpropylamine (0.04 mL) gave the titlecompound; ¹H NMR (d₆-DMSO) δ 9.53 (1H, s), 8.49 (1H, bs), 8.18 (1H, d),7.88 (4H, dd), 7.70 (1H, d), 7.32 (1H, bs), 6.35 (1H, bs), 2.30 (6H,bs), 1.66 (2H, bs), 1.48 (4H, bs), 1.37 (2H, bs); m/z 549 (M+1)⁺.

Example 113N-{4-[2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-(3-piperidin-1-ylpropyl)amine

[0644]

[0645] In an analogous procedure to Example 104,4-[2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-ylmethyl sulfone (0.02 g), 3-piperidin-1-ylpropylamine (0.04 mL) gave thetitle compound; ¹H NMR (d₆-DMSO) δ 9.51 (1H, s), 8.49 (1H, bs), 8.20(1H, d), 7.86 (1H, dd), 7.71 (1H, d), 7.65 (1H, m), 7.58 (1H, dd), 7.34(1H, bs), 6.41 (1H, bs), 3.29 (2H, bm), 2.31 (4H, bs), 1.69 (2H, bs),1.49 (4H, bm), 1.39 (2H, bm); m/z 533 (M+1)⁺.

Example 114N-{4-[2-(3-chlorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-(3-piperidin-1-ylpropyl)amine

[0646]

[0647] In an analogous procedure to Example 104,4-[2-(3-chlorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-ylmethyl sulfone (0.02 g) and 3-piperidin-1-ylpropylamine (0.04 mL) gavethe title compound; ¹H NMR (d₆-DMSO) δ 9.51 (1H, s), 8.49 (1H, bs), 8.16(1H, d), 7.72-7.65 (2H, m), 7.617.51 (3H, m), 7.33 (1H, bs), 6.31 (1H,bs), 3.29 (2H, bs), 2.3 (6H, bs), 1.69 (2H, m), 1.47 (4H, bs), 1.36 (2H,m); m/z 515(M+1)+.

Example 115N-(2-azepan-1-ylethyl)-N-(4-{6-(trifluoromethyl)-2-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyridin-3-yl}pyrimidin-2-yl)amine

[0648]

[0649] In an analogous procedure to Example 104, methyl4-{6-(trifluoromethyl)-2-(4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyridin-3-yl}pyrimidin-2-ylsulfone (0.02 g) and 2-azepan-1-ylethylamine (0.04 mL) gave the titlecompound ¹H NMR (d₆-DMSO) δ 9.54 (1H, s), 8.49 (1H, bs), 8.20 (1H, d),7.89 (4H, dd), 7.70 (1H, d), 6.99 (1H, bs), 6.40 (1H, bs), 2.60 (4H,bs), 1.54 (8H, bs); m/z 450, 549 (M+1)⁺.

Example 116N-(2-azepan-1-ylethyl)-N-{4-[2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}amine

[0650]

[0651] In an analogous procedure to Example 104,4-[2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-ylmethyl sulfone (0.02 g) and 2-azepan-1-ylethylamine (0.04 mL) gave thetitle compound; ¹H NMR (d₆-DMSO) δ 9.50 (1H, s), 8.46 (1H, bs), 8.20(1H, d), 7.84 (1H, dd), 7.68 (1H, dd), 7.62 (1H, m), 7.56 (1H, dd), 7.00(1H, bs), 6.44 (1H, bs), 2.58 (4H, bs), 1.54 (8H, bs); m/z 533 (M+1)+.

Example 117N-(2-azepan-1-ylethyl)-N-{4-[2-(3-chlorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}amine

[0652]

[0653] 2-Azepan-1-ylethylamine (0.04 mL) and4-[2-(3-chlorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-ylmethyl sulfone (0.02 g) were mixed at room temperature and heated withan airgun until a homogenous melt was obtained (2 min). Upon cooling,water was added. The precipitated solid was filtered and dried to givethe title compound as a beige solid (0.014 g); ¹H NMR (d₆-DMSO) δ 9.51(1H, s), 8.49 (1H, bs), 8.16 (1H, d), 7.70-7.65 (2H, m), 7.60-7.50 (3H,m), 7.00 (1H, bs), 6.36 (1H, bs), 2.6 (6H, bs), 1.6 (8H, bs); m/z515(M+1)⁺.

Example 118N-{4-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-(2-morpholin-4-ylethyl)amine

[0654]

[0655] In an analogous procedure to Example 117,4-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-ylmethyl sulfone (0.02 g) and 2-morpholin-4-ylethylamine (0.04 mL) gavethe title compound; ¹H NMR (CDCl₃) δ 8.83 (1H, s), 8.50 (1H, d), 8.14(1H, d), 7.61 (2H, dd), 7.43 (1H, dd), 7.16 (2H, dd), 6.37 (1H, d), 5.72(1H, bs), 3.76 (4H, t), 3.58 (2H, ddd), 2.67 (2H, t), 2.53 (4H, m); m/z487 (M+1)⁺.

Example 119N-(2-morpholin-4-ylethyl)-N-(4-{6-(trifluoromethyl)-2-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyridin-3-yl}pyrimidin-2-yl)amine

[0656]

[0657] In an analogous procedure to Example 117, methyl4-{6-(trifluoromethyl)-2-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyridin-3-yl}pyrimidin-2-ylsulfone (0.02 g) and 2-morpholin-4-ylethylamine (0.04 mL) gave the titlecompound; ¹H NMR (d₆-DMSO) δ 9.52 (1H, s), 8.48 (1H, bs), 8.19 (1H, d),7.86 (4H, dd), 7.70 (1H, d), 7.07 (1H, bs), 6.39 (1H, bs), 3.56 (4H,bt), 2.44 (2H, bs), 2.36 (4H, bs); m/z 537 (M+1)⁺.

Example 120N-{4-[2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-(2-morpholin-4-ylethyl)amine

[0658]

[0659] In an analogous procedure to Example 0.117,4-[2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-ylmethyl sulfone (0.02 g) and 2-morpholin-4-ylethylamine (0.04 mL) gavethe title compound; ¹H NMR (d₆-DMSO) δ 9.50 (1H, s), 8.47 (1H, bs), 8.18(1H, d), 7.83 (1H, dd), 7.69 (1H, d), 7.62 (1H, m), 7.57 (1H, dd), 7.09(1H, bs), 6.42 (1H, bs), 3.57 (4H, bt), 2.45 (2H, bs), 2.37 (4H, bs);m/z 521 (M+1)⁺.

Example 121N-(3-morpholin-4-ylpropyl)-N-(4-{6-(trifluoromethyl)-2-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyridin-3-yl}pyrimidin-2-yl)amine

[0660]

[0661] In an analogous procedure to Example 117, methyl4-{6-(trifluoromethyl)-2-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyridin-3-yl}pyrimidin-2-ylsulfone (0.02 g) and 3-morpholin-4-ylpropylamine (0.04 mL) gave thetitle compound; ¹H NMR (d₆-DMSO) δ 9.54 (1H, s), 8.49 (1H, bs), 8.19(1H, d), 7.87 (4H, dd), 7.72 (1H, d), 7.29 (1H, bs), 6.38 (1H, bs), 3.56(4H, bs), 2.34 (6H, bs), 1.68 (2H, bs); m/z 551 (M+1)⁺.

Example 122N-{4-[2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-(3-morpholin-4-ylpropyl)amine

[0662]

[0663] In an analogous procedure to Example 117,4-[2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-ylmethyl sulfone (0.02 g) and 3-morpholin-4-ylpropylamine (0.04 mL) gavethe title compound; ¹H NMR (d₆-DMSO) δ 9.51 (1H, s), 8.47 (1H, bs), 8.19(1H, d), 7.85 (1H, dd), 7.71 (1H, d), 7.64 (1H, m), 7.58 (1H, dd), 7.30(1H, bs), 6.41 (1H, bs), 3.57 (4H, bs), 2.35 (6H, bs), 1.69 (2H, bs);m/z 535 (M+1)⁺.

Example 123N-{4-[2-(3-chlorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-(3-morpholin-4-ylpropyl)amine

[0664]

[0665] In an analogous procedure to Example 117,4-[2-(3-chlorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-ylmethyl sulfone (0.02 g) and 3-morpholin-4-ylpropylamine (0.04 mL) gavethe title compound; ¹H NMR (d₆-DMSO) δ 9.51 (1H, s), 8.49 (1H, bs), 8.16(1H, d), 7.72-7.65 (2H, m), 7.617.51 (3H, m), 7.30 (1H, bs), 6.35 (1H,bs), 3.55 (4H, bs), 2.33 (6H, bs), 1.69 (2H, m); m/z 517(M+1)⁺.

Example 124N-{4-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-[3-(4-methylpiperazin-1-yl)propyl]amine

[0666]

[0667] To a mixture of the enamine described in Example 87f (5.45 g,14.45 mmol) and N-(3-(4-methylpiprazino)propyl)guanidine hydrogensulfate (12.88 g, 3.0 equiv, 43.4 mmol) in anhydrous DMF (50 mL) undernitrogen was added powdered K₂CO₃ (2.75 g, 5.0 equiv, 20.0 mmol). Themixture was stirred and heated at 130° C. for 37 h and then filteredthrough a glass fritted funnel while warm. The solvent was evaporatedunder reduced pressure and the residue was triturated with EtOAc/Hexanes(1:10) to afford a solid that was collected by filtration and driedunder vacuum to give the desired product as an off-white solid, 5.0 g(67%). ¹H NMR (CDCl₃) δ 1.85 (m, 2H), 2.30 (s, 3H), 2.53 (m, 10H), 3.54(m, 2H), 6.00 (br s, 1H), 6.30 (d, 1H), 7.14 (m, 2H), 7.40 (d, 1H), 7.60(m, 2H), 8.08 (d, 1H), 8.49 (d, 1H), 8.81 (s, 1H). MS (ESI+) m/z 514.19(M⁺+H).

Example 125N-{4-[2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyrazolo-[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-[3-(4-methylpiperazin-1-yl)propyl]amine

[0668]

[0669] In an analogous procedure to Example 117,4-[2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-ylmethyl sulfone (0.02 g) and 3-(4-methylpiperazin-1-yl)propylamine (0.04mL) gave the title compound; ¹H NMR (d₆-DMSO) δ 9.52 (1H, s), 8.48 (1H,bs), 8.19 (1H, d), 7.86 (1H, dd), 7.71 (1H, d), 7.64 (1H, m), 7.58 (1H,dd), 7.30 (1H, bs), 6.40 (1H, bs), 3.31 (2H, bs), 2.33 (8H, bm), 2.14(3H, bs), 1.68 (2H, bs); m/z 548 (M+1)⁺.

Example 126N-{4-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-[2-(4-methylpiperazin-1-yl)ethyl]amine

[0670]

[0671] 2-(4-Methylpiperazin-1-yl)ethyl]amine hydrochloride (0.058 g) and4-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-ylmethyl sulfone (0.02 g) in dimethylformamide (0.5 mL) were treated withpotassium carbonate (0.064 g) and heated at 50° C. for 16 h. Uponcooling, water was added. The precipitated solid was filtered and driedto give the title compound as a white solid (0.01 g); ¹H NMR (CDCl₃) δ8.82 (1H, s), 8.50 (1H, d), 8.12 (1H, d), 7.65 (2H, m), 7.45 (1H, d),7.15 (2H, m), 6.36 (1H, d), 5.70 (1H, bs), 3.58 (2H, ddd), 2.66 (2H, t),2.55 (8H, m), 2.30 (3H, s); m/z 500 (M+1)⁺.

Example 127N-[2-(4-propylpiperazin-1-yl)ethyl]-N-(4-{6-(trifluoromethyl)-2-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyridin-3-yl}pyrimidin-2-yl)amine

[0672]

[0673] In an analogous procedure to Example 117,methyl{6-(trifluoromethyl)-2-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyridin-3-yl}pyrimidin-2-ylsulfone (0.02 g) and 2-(4-propylpiperazin-1-yl)ethylamine (0.04 mL) gavethe title compound; ¹H NMR (d₆-DMSO) δ 9.53 (1H, s), 8.46 (1H, bs), 8.18(1H, d), 7.87 (4H, dd), 7.69 (1H, d), 7.03 (1H, bs), 6.39 (1H, bs),2.46-2.27 (8H, bm), 2.20 (2H, t), 1.42 (2H, m), 0.83 (3H, t); m/z 450,578 (M+1)⁺.

Example 128N-{4-[2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyrazolo-[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-[2-(4-propylpiperazin-1-yl)ethyl]amine

[0674]

[0675] In an analogous procedure to Example 117,4-[2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-ylmethyl sulfone (0.02 g) and 2-(4-propylpiperazin-1-yl)ethylamine (0.04mL) gave the title compound; ¹H NMR (d₆-DMSO) δ 9.51 (1H, s), 8.50 (1H,bs), 8.20 (1H, d), 7.84 (1H, d), 7.72 (1H, d), 7.63 (1H, m), 7.57 (1H,dd), 7.04 (1H, bs), 6.43 (1H, bs), 2.52-2.25 (8H, bm), 2.20 (2H, t),1.42 (2H, m), 0.85 (3H, t); m/z 562 (M+1)⁺.

Example 129N-{4-[2-(3-chlorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-[2-(4-propylpiperazin-1-yl)ethyl]amine

[0676]

[0677] In an analogous procedure to Example 117,4-[2-(3-chlorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-ylmethyl sulfone (0.02 g) and 2-(4-propylpiperazin-1-yl)ethylamine (0.04mL) gave the title compound; ¹H NMR (d₆-DMSO) δ 9.51 (1H, s), 8.51 (1H,bs), 8.16 (1H, d), 7.72-7.64 (2H, m), 7.627.50 (3H, m), 7.04 (1H, bs),6.36 (1H, bs), 2.35 (8H, m), 2.19 (2H, t), 1.4 (2H, q), 0.83 (3H, t);m/z 544(M+1)⁺.

[0678] p38 Kinase Assay

[0679] The peptide substrate used in the p38 assay wasbiotin-IPTSPITTTYFFFRRR-amide. The p38 and MEK6 proteins were purifiedto homogeneity from E. coli expression systems. The fusion proteins weretagged at the N-terminus with Glutathione-S-Transferase (GST). Themaximum activation was achieved by incubating 20 uL of a reactionmixture of 30 nM MEK6 protein and 120 nM p38 protein in the presence of1.5 uM peptide and 10 mM Mg (CH₃CO₂)₂ in 100 mM HEPES₇ pH 7.5, added to15 uL of a mixture of 1.5 uM ATP with 0.08 uCi [g-³³P]ATP, with orwithout 15 uL of inhibitor in 6% DMSO. The controls were reactions inthe presence (negative controls) or absence (positive controls) of 50 mMEDTA. Reactions were allowed to proceed for 60 min at room temperatureand quenched with addition of 50 uL of 250 mM EDTA and mixed with 150 uLof Streptavidin SPA beads (Amersham) to 0.5 mg/reaction. The DynatechMicrofluor white U-bottom plates were sealed and the beads were allowedto settle overnight. The plates were counted in a Packard TopCount for60 seconds. IC₅₀ values were obtained by fitting raw data to %I=100*(1−(I−C2)/(C1−C2)), where I was CPM of background, C1 was positivecontrol, and C2 was negative control.

[0680] JNK3 Kinase Assay Jnk-3alpha-2 (as a truncated construct,residues 39 to 224) was expressed in E. coli as a GST fusion protein.Following purification the GST portion was removed by thrombin cleavage.The enzyme was stored at −80° C. Substrate c-Jun was expressed as a GSTfusion protein including a signal peptide (biotinylation site) in E.coli. Following purification the substrate was biotinylated on aspecific lysine in the signal peptide using biotin ligase. Prior toassay Jnk-3 was pre-activated by incubation with MgATP. The enzyme (10nM) was screened in 40 mM HEPES (pH 7.4), 150 mM NaCl, 20 mMglycerophosphate, 1 mM DTT, 0.2 mM vanadate, 200 nM biotin-c-Jun, 5 mMMgCl₂ and 10 uM ATP. Inhibitors were added over a conc range of from 0to 10 uM in DMSO (fc 3%). The reaction was stopped by the addition of 25mM EDTA. Phospho-c-Jun was detected using homogeneous time resolvedfluorescence (HTRF) with a Eu-labelled antiphosphoserine (Serine 73) andstreptavidin APC.

[0681] Cell Based Assay for Cytokines Production in PBMNC

[0682] Human peripheral blood mononuclear cells were isolated fromheparinized blood by LSM (Organon Teknika) from volunteer donors.Purified human peripheral blood mononuclear cells were then suspended ata concentration of 2×10⁶ cells/ml in RPMI 1640 medium supplemented with10% heat-inactivated FBS and 1% antibiotics. Aliquots of 100 μl (2×10⁵cells) were added to 96-well microliter plates. Test compounds at 0.1nM-10 mM dose ranges (final-DMSO concentration in culture medium was0.1%) were then added to the cells for 10-15 minutes before the additionof lipopolysaccharide (1 ng/ml). After incubation at 37° C. in a 5% CO₂incubator for 18-20 h, cell free supernatants were collected bycentrifugation at 800 g. The supernatant was then assayed for the amountof TNFα and IL-1β by using Quantikine immunoassay kits developed by R&DSystems (Minneapolis, Minn.).

[0683] Murine LPS—Stimulated Serum TNF Inhibition Protocol

[0684] The potency of compounds of the invention as inhibitors of serumTNFα elevation in mice treated with lipopolysaccharide (LPS) wasdetermined as follows; a) for subcutaneous (s.c.) administration, testcompound was dissolved in DMSO and added to a mixture of 0.9% sodiumchloride solution and 30% Trappsol HPB-20 (Cyclodextrin TechnologyDevelopment Inc., Gainesville, Fla. USA) for a final DMSO concentrationof 1%. The dosing solution was sonicated briefly and 0.2 mL was injectedsubcutaneously 10 min prior to LPS injection; b) for per oral (p.o.)administration, test compounds were formulated in 0.2 mL of PBS and 0.1%Tween 80 and given orally via gavage 10 min prior to LPS administration.

[0685] C3/hen female mice were injected intraperitoneally with 200 μg/kgLPS (Escherichia coil, Serotype 0111:B4, Sigma Chemical Co, St. Louis,Mo.) in PBS and sacrificed 90 min later by CO₂ asphyxiation. Blood wasimmediately taken from the caudal vena cava and plasma prepared andfrozen at −80° C. Plasma concentrations of TNF were measured by ELISA(Genzyme Co., Cambridge Mass.).

[0686] Cell Based Efficacy (MTT Assay)

[0687] The potency of compounds of the invention are tested for theirability to inhibit cell proliferation and cell viability. The metabolicconversion of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT, Sigma #M2128) to a reduced form was a commonly usedmeasure of cellular viability. Following was the procedure:

[0688] Cells are maintained in 75 cm² tissue culture flasks until readyfor use. The cells are grown and plated for the assay in Dulbecco'smodified Eagle's media containing 10% fetal bovine serum. For example,the following cell lines can be used: a) human foreskin fibroblasts(HFF), b) HT29 (human colon carcinoma cell line), c) MDA-MB468 (humanbreast carcinoma cell line), d) RKO (human colon adenocarcinoma cellline), e) SW620 (human colon carcinoma cell line), f) A549 (human lungcarcinoma cell line), and g) MIA PACA (human pancreatic carcinoma cellline). Cells are maintained at 37° C. in 10% CO₂, 90% humidified air.Cells are plated in 96-well tissue culture plates at the densitieslisted below (Table 6). 100 μL of cell suspension was added to each wellof the 96-well plate except the top row of the plate which contains nocells and serves as a reference for the spectrophotometer. TABLE 6 Cellline Density HFF 2500 cells/well HT29 cell lines 2500 cells/wellMDA-MB-468 cell line 5000 cells/well SW620 4000 cells/well MIA PACA 3000cells/well PC-3 4500 cells/well

[0689] Cells are incubated overnight in Dulbecco's modified Eagle'smedia containing 10% fetal bovine serum at 37° C in 10% CO₂, 90%humidified air prior to dosing. Cells are dosed in 10 sequential 3-folddilutions starting at 30 μM depending upon the solubility of thecompound. Compounds with solubilities of less than 30 μM are dosed atthe highest soluble concentration. Stock solutions of compounds are madein 100% dimethyl sulfoxide (DMSO). Stock solutions are diluted inDulbecco's modified Eagle's media containing 100 ug/mL gentamicin and0.3 to 0.6% DMSO at the twice the highest concentration to be placed onthe cells. If compounds have been dissolved in DMSO the finalconcentration of DMSO on the cells was kept below 0.3%. 3-fold serialdilutions are performed on each compound to prepare 10 concentrations ofthe compound for dosing. 100 μL of diluted compound was added to the 100μL of media currently on the dish. For each concentration of compound,2-4 replicate wells are prepared.

[0690] Cells are returned to incubator and allowed to proliferate in thepresence of compound for 72 h before addition of MTT. MTT was preparedin phosphate buffered saline (Irvine Scientific #9240) at aconcentration of 2 mg/mL. 50 μL per well of MTT solution was added tothe 200 μL of media to yield a final concentration of 0.4 mg/mL andplates are returned to the incubator for 4 h. After 4 h incubation themedia, compound and MTT mixture was aspirated from the plates and 100 μLof 100% DMSO was added to each well in addition to 25 uL of Sorenson'sBuffer (0.1M glycine, 0.1M NaCl, pH 10.5). Quantitation of metabolicreduction of MTT in each plate was performed by reading optical densityat 570 nm wavelength on a Molecular Devices UV max microplate reader.Growth inhibition curves and 50% inhibitory concentrations aredetermined using Microsoft Excel.

[0691] Representative data for compounds of the current inventionwherein Z is CH are given in Table 7. The columns in Table 7 refer tothe compound by Example #, inhibition of p38 kinase (IC₅₀), inhibitionof TNF release from human peripheral blood mononuclear cells (PBMNC)following stimulation with LPS (IC₅₀), % inhibition of murine TNFproduction in mice following an LPS challenge and cytotoxicity towardthe HFF cell line (IC₅₀). TABLE 7 Example # P38 kinase TNF/PBMNC % inh.(dose) HFF 1 + + 65 (30 mpk) ++++ 5 ++ ++ 11 (30 mpk) NT 6 + NT NT NT16 + + NT ++++ 23 + + NT NT 30 + + 45 (30 mpk) ++++ 31 + + 42 (30 mpk)NT 37 + + NT +++

[0692] Representative data for compounds of the current inventionwherein Z is N are given in Table 8. The columns in Table 8 refer to thecompound by Example #, Inhibition of p38 kinase (IC₅₀), inhibition ofJNK3 kinase (IC₅₀), inhibition of TNF release from human peripheralblood mononuclear cells (PBMNC) following stimulation with LPS (IC₅₀), %inhibition of murine TNF production in mice following an LPS challengeand cytotoxicity toward the HFF cell line (IC₅₀). TABLE 8 Example p38JNK3 # kinase kinase TNF/PBMNC % inh. (dose) HFF 56 ++ NT ++ 67% (30mpk) ++++ 57 + NT + 56% (30 mpk) NT 60 + NT + 88% (30 mpk) NT 61 + + NTNT NT 64 + NT + 62% (30 mpk) NT 65 + NT NT NT NT 68 + + + 24% (30 mpk)NT 69 + NT + 45% (30 mpk) NT 72 + NT NT NT NT 73 + + + 52% (30 mpk) NT75 + + + 90% (30 mpk) NT 76 + NT NT NT NT 79 + NT NT NT NT 80 + NT + NTNT 82 + NT + 87% (30 mpk) NT 84 + + NT NT NT 86 + + NT NT NT

[0693] Key (Tables 7 and 8) Symbol Range + <0.5 μM ++ 0.5-5 μM +++ 5-50μM ++++ >50 μM NT Not Tested

[0694] Results for p38 assays (using Assay II above) and JNK 3 assaysare given for further examples in Table 9 below: TABLE 9 Example # JNK3IC50 p38 IC50 87 + ++ 88 + + 89 + +++ 90 + +++ 93 ++ +++ 94 ++ +++ 95 +96 ++ 97 + 98 + ++ 99 + ++ 100 + ++ 103 + 104 + ++ 105 + ++ 106 ++ +++108 + 109 + ++ 110 + ++ 112 + + 113 ++ ++ 116 + ++ 117 + ++ 119 + 120 +++++ 121 + 122 ++ ++ 123 ++ +++ 124 ++ +++ 125 ++ +++ 127 + + 128 ++ +++129 ++ +++

[0695] The application of which this description and claims forms partmay be used as a basis for priority in respect of any subsequentapplication. The claims of such subsequent application may be directedto any feature or combination of features described herein. They maytake the form of product, composition, process or use claims and mayinclude, by way of example and without limitation, one or more of thefollowing claims:

1. A compound of Formula (I):

or a salt or solvate thereof or a physiologically functional derivativethereof: wherein Z is CH or N; a is 1 or 2; b is 1, 2 or 3; c is 1, 2 or3; each R¹ is independently selected from groups of the formula—(X)_(d)—(CH₂)_(e)—R⁵ wherein d is 0 or 1; e is 0 to 6; X is O, NR⁶ orS(O)_(f) where f is 0, 1 or 2; R⁵ is hydrogen, halogen, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₂cycloalkyl, heterocyclyl, aryl,heteroaryl, hydroxyl, cyano, nitro, trihalomethyl, NR⁷R⁸, C₆H₄NR⁷R⁸,C₆H₄(CH₂)NR⁷R⁸, C(O)R⁷, C(O)NR⁷R⁸, OC(O)R⁷, OC(O)NR⁷R⁸, CO₂R⁷, OCO₂R⁷,SO₂R⁷, SO₂NR⁷R⁸, C(═NR⁷)NR⁷R⁸, NR⁷(C═NR⁷)NR⁷ R⁸ NHC(O)R⁷ orN(C₁₋₃alkyl)C(O)R⁷; each R² is independently selected from hydrogen,cyano, halogen, trihalomethyl, OC₁₋₆alkyl, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, S(O)_(g)C₁₋₆alkyl where g is 0, 1 or 2,NC₁₋₆alkyl(C₁₋₆alkyl), hydroxyl or nitro; each R⁴ is independentlyselected from groups of the formula —(Y)_(d)—(CH₂)_(e)—R³ wherein d is 0or 1; e is 0 to 6; Y is O or S(O)_(f) where f is 0, 1 or 2; R³ ishydrogen, halogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₂cycloalkyl,heterocyclyl, aryl, heteroaryl, hydroxyl, cyano, nitro, trihalomethyl,phthalamido, C₆H₄NR⁷R⁸, C₆H₄(CH₂)NR⁷R⁸, C(O)R⁷, C(O)NR⁷R⁸, OC(O)R⁷,OC(O)NR⁷R⁸, CO₂R⁷, OCO₂R⁷, SO₂R⁷, SO₂NR⁷R⁸ or C(═NR⁷)NR⁷R⁸; R⁶ is H,C₁₋₆alkyl, C₂₋₆alkenyl, aryl, heteroaryl, C₃₋₁₂cycloalkyl, orheterocyclyl; R⁷ and R⁸ are each independently H, C₁₋₈alkyl,C₂₋₆alkenyl, SO₂C₁₋₆alkyl, (CH₂)_(m)—C₃₋₁₂cycloalkyl, (CH₂)_(m)-aryl,(CH₂)_(m)-heterocyclyl, (CH₂)_(m)-heteroaryl, wherein m=0, 1 or 2, ormay, together with the nitrogen atom to which they are bound, form aheterocyclyl group; and wherein any of said alkyl, alkenyl and alkynylgroups may be optionally substituted with up to three members selectedfrom halogen, hydroxyl, oxo, cyano, NR⁷R⁸, C₁₋₆alkyl, OC₁₋₆alkyl,S(O)C₁₋₆alkyl, S(O)₂C₁₋₆alkyl and SO₂NR⁷R⁸; and wherein any of saidcycloalkyl, heterocyclyl, aryl, and heteroaryl groups may be optionallysubstituted with substituents selected from a group consisting ofC₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkylsulfenyl, C₁₋₆alkylsulfinyl,C₁₋₆alkylsulfonyl, hydroxy, oxo, mercapto, nitro, cyano, halogen,C₁₋₆perfluoroalkyl, amino optionally substituted by C₁₋₆alkyl, carbamoyloptionally substituted by C₁₋₆alkyl, NR⁷R⁸, carboxy and aminosulfonyloptionally substituted by C₁₋₆alkyl; with the proviso that (R²)_(b),(R¹)_(a) and (R⁴)_(c) cannot all represent solely hydrogen substitution;and with the proviso that when (R²)_(b) represents solely hydrogen ormethyl substitution, (R⁴)_(c) cannot represent solely hydrogensubstitution; and with the proviso that R⁴ may not be located on the7-position of the pyrazolopyridine ring system as numbered below:


2. A compound of formula (I) according to claim 1 wherein Z is N.
 3. Acompound of formula (I) according to claim 1 or 2 wherein a is
 1. 4. Acompound of formula (I) according to any one of the preceding claimswherein R¹ is in the 2-position of the pyridyl or pyrimidinyl ring.
 5. Acompound of formula (I) according to any one of the preceding claimswherein R¹ is —NR⁶—(CH₂)_(e)—R⁵.
 6. A compound of formula (I) accordingto any one of the preceding claims wherein b is
 1. 7. A compound offormula (I) according to any one of the preceding claims wherein R² isselected from hydrogen, cyano, halogen, trihalomethyl and OC₁₋₆alkyl. 8.A compound of formula (I) according to any one of the preceding claimswherein R² is fluoro.
 9. A compound of formula (I) according to any oneof the preceding claims wherein R² is in the 4-position of the phenylring.
 10. A compound of formula (I) according to any one of thepreceding claims wherein c is
 1. 11. A compound of formula (I) accordingto any one of the preceding claims wherein R⁴ is in the 6-position ofthe pyrazolopyridine ring.
 12. A compound of formula (1) according toany one of the preceding claims wherein R⁴ is selected from C₁₋₆alkyl,halogen, cyano and trihalomethyl.
 13. A compound of formula (I) asdescribed in any one of Examples 1 to
 129. 14.3-(4-[2-(4-Fluorophenyl)-6-trifluoromethylpyrazolo[1, 5-a]pyridin-3-yl]-2-pyrimidinylamino)-1-propanol or a salt or solvate thereof, ora physiologically functional derivative thereof.
 15. A pharmaceuticalcomposition comprising a compound of formula (I) or a salt or solvatethereof, or a physiologically functional derivative thereof, accordingto any one of claims 1 to 14, in admixture with one or morepharmaceutically acceptable carriers, diluents or excipients.
 16. Acompound of formula (I) or a salt or solvate thereof, or aphysiologically functional derivative thereof, according to any one ofclaims 1 to 14, for use in therapy.
 17. Use of a compound of formula (I)or a salt or solvate thereof, or a physiologically functional derivativethereof, according to any one of claims 1 to 14, for the preparation ofa medicament for the treatment of a condition or disease state mediatedby p38 kinase activity or mediated by cytokines produced by the activityof p38 kinase.
 18. Use of a compound of formula (I) or a salt or solvatethereof, or a physiologically functional derivative thereof, accordingto any one of claims 1 to 14 for the preparation of a medicament for thetreatment of a condition or disease state mediated by JNK kinaseactivity or mediated by cytokines produced by the activity of JNKkinase.
 19. Use of a compound of formula (I) or a salt or solvatethereof, or a physiologically functional derivative thereof, accordingto any one of claims 1 to 14, for the preparation of a medicament forthe simultaneous treatment of two or more conditions or disease statesindependently mediated by p38 and JNK kinase activity or independentlymediated by cytokines produced by the activity of p38 and JNK kinase.20. A method of treating a condition or disease state mediated by p38kinase or mediated by cytokines whose production is mediated by p38kinase activity in a subject, which comprises administering to saidsubject a therapeutically effective amount of a compound of formula (I)or a pharmaceutically acceptable salt or solvate thereof or aphysiologically functional derivative thereof according to any one ofclaims 1 to
 14. 21. A method of treating a condition or disease statemediated by JNK kinase or mediated by cytokines whose production ismediated by JNK kinase activity in a subject, which comprisesadministering to said subject a therapeutically effective amount of acompound of formula (I) or a pharmaceutically acceptable salt or solvatethereof or a physiologically functional derivative thereof according toany one of claims 1 to
 14. 22. A method of treating two or moreconditions or diseases independently mediated by p38 and JNK kinaseactivity or independently mediated by cytokines produced by the activityof p38 and JNK kinase which comprises administering to said subject atherapeutically effective amount of a compound of formula (I) or a saltor solvate thereof, or a physiologically functional derivative thereofaccording to any one of claims 1 to 14.